Sequential Mannich-aza-Michael reactions for the stereodivergent synthesis of highly substituted pyrrolidines

Article abstract of DOI:10.1002/ejoc.200900787

A stereodivergent synthesis of 2,3,5-trisubstituted pyrrolidines by an organocatalytic Mannich/aza-Michael addition sequence has been developed. Depending upon the choice of the base used in the intramolecular aza-Michael additions, 2,5-trans- or 2,5-cis-configured pyrrolidines were obtained in high yields and excellent diastereomeric ratios. Selective deprotection of the amino group and the side-chain hydroxy group proceeded without loss of diastereomeric purity. The stereodivergent outcome of the key aza-Michael reactions is the result of thermodynamically versus kinetically controlled cyclization.

Full text of DOI:10.1002/ejoc.200900787

FULL PAPER
DOI: 10.1002/ejoc.200900787
Sequential Mannich-Aza-Michael Reactions for the Stereodivergent Synthesis
of Highly Substituted Pyrrolidines
Charlotte Enkisch[a] and Christoph Schneider*[a]
Keywords: Asymmetric catalysis / Michael addition / Mannich reactions / Nitrogen heterocycles / Organocatalysis / Proline
A stereodivergent synthesis of 2,3,5-trisubstituted pyrrolid-
ines by an organocatalytic Mannich/aza-Michael addition
group proceeded without loss of diastereomeric purity. The
stereodivergent outcome of the key aza-Michael reactions is
sequence has been developed. Depending upon the choice the result of thermodynamically versus kinetically controlled
of the base used in the intramolecular aza-Michael additions,
2,5-trans- or 2,5-cis-configured pyrrolidines were obtained in
high yields and excellent diastereomeric ratios. Selective de-
protection of the amino group and the side-chain hydroxy
cyclization.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Organocatalytic reactions that have emerged recently[11] fa-
N-Heterocyclic compounds are common structural cilitate the sequential approach, because they can be used
features in a variety of biologically active substances. In to make the ring closures enantioselective[12] and/or help to
particular, substituted pyrrolidines are found in many natu- achieve the efficient enantioselective preparation of the
ral products, such as kainic acid,[1] alkaloids such as (–)- open-chain molecules.[13] For the diastereoselective ring-clo-
codonopsinine,[2] and the family of the broussonetines,[3] as sure reactions, intramolecular aza-Michael additions have
well as in a number of synthetic drugs that interact with a recently attracted considerable attention.[13b,14] An intramo-
plethora of target enzymes such as acetylcholinesterase,[4] lecular aza-Michael addition, for instance, has been used
hepatitis C virus RNA polymerase,[5] influenza neuramin- as the key step in the synthesis of (3R,5R)-carbapenam-3-
idase,[6] and HIV-1 protease.[7] The broad range of bio- carboxylic acid.[14h] Moreover, it has been suggested that
logical activity of highly functionalized pyrrolidines under- aza-Michael additions also occur in biosynthetic pathways,
lines the importance of having a broad range of versatile such as in the suggested biosynthesis of plakoridine A.[15]
and efficient stereoselective preparation methods readily
We recently achieved the stereoselective synthesis of
available. Two main strategies for the stereoselective prepa- highly substituted piperidines by a similar approach
ration of highly substituted pyrrolidines have evolved:[8] (Scheme 1).[16] The functionalized aldehydes 1, obtained in
either asymmetric 1,3-dipolar cycloadditions[9] or sequen- enantiomerically pure form through Cope rearrangements
tial approaches in which linear molecules containing the of silylated syn-aldol products,[17] were treated with glyoxyl
stereocenters are built up first, followed by cyclization.[2,10] imines and catalytic amounts of -proline, resulting in a
Scheme 1. Mannich/aza-Michael approach for the synthesis of functionalized piperidines (PMP: p-methoxyphenyl).[16]
[a] Institut für Organische Chemie, Universität Leipzig,
highly stereoselective domino-Mannich/aza-Michael reac-
tion sequence and the formation of pipecolic esters in one
step.
Johannisallee 29, 04103 Leipzig, Germany
Fax: +49-341-9736599
E-mail: schneider@chemie.uni-leipzig.de
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C. Enkisch, C. Schneider
FULL PAPER
Scheme 2. Mannich/aza-Michael approach for the synthesis of highly functionalized pyrrolidines.
We have now extended this methodology to the highly try 6), which was obtained in 44% yield and 82% ee. Si-
diastereoselective preparation of trisubstituted pyrrolidines lylation of the hydroxy group was achieved with tert-butyld-
through a Mannich/aza-Michael sequence with the 6-oxo- imethylsilyl chloride (TBSCl), imidazole, and 4-(dimeth-
2-enoate 2 as starting compound (Scheme 2). As a special ylamino)pyridine (DMAP) in yields ranging from 70 to
bonus we can easily control the 2,5-cis/trans diastereoselec- 99% (Scheme 4).
tivity of the aza-Michael cyclizations by using the appropri-
ate base under carefully optimized reaction conditions.
Table 1. -Proline-catalyzed Mannich reactions with aldehyde 2
(Scheme 3).
Entry
Ar
Product
Yield [%][a]
ee [%][b]
Results and Discussion
1
2
3
4
5
6
7
8
Ph
4-FC6H5
4a
4b
4c
4d
4e
4f
82
80
83
58
76
44
97
63
99
99
99
99
99
82
99
98
Asymmetric Organocatalytic Mannich Reactions
4-ClC6H5
4-MeOC6H5
4-CH3C6H5
3-CH3C6H5
2-CH3C6H5
2-furyl
In the first step of the envisioned sequence, asymmetric
proline-catalyzed Mannich reactions with N-Boc-imines ac-
cording to the protocol developed by List et al.[18] were em-
ployed to establish the absolute and relative configurations
at C2 and C3 (pyrrolidine numbering; Scheme 2). Thus, the
aldehyde 2, prepared by a Wittig reaction between succinal-
dehyde and ethoxycarbonyltriphenylphosphorane,[19] was
treated with N-Boc-protected imines in the presence of -
proline (20 mol-%), followed by in situ reduction of the car-
bonyl group with sodium borohydride and acetic acid
(Scheme 3). In order to achieve complete conversion, a sec-
ond equivalent of the imine was added after 6–7 h.
4g
4h
[a] Yield of isolated diastereomerically pure sample after flash col-
umn chromatography. [b] Determined by chiral HPLC analysis.
Base-Promoted Intramolecular Aza-Michael Additions
In an attempt to avoid the use of protecting groups, cycli-
zation of the Mannich products was first attempted without
By the above two-step sequence, a variety of aromatic N- prior protection of the hydroxy group. However, under vari-
Boc-protected imines were treated with aldehyde 2, giving ous reaction conditions the formation of tetrahydrofurans
rise to the reduced Mannich products typically in good resulting from the undesired oxa-Michael addition could
yields (Table 1). These products were generally obtained as not be suppressed completely. Accordingly the O-silylated
single diastereomers with excellent enantioselectivities, the Mannich products were used instead (Scheme 5 and
only exception being the 3-methylphenyl derivative 4f (En- Table 2).
Scheme 3. -Proline-catalyzed Mannich reactions with aldehyde 2.
Scheme 4. Silylation of the Mannich products.
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Stereodivergent Synthesis of Highly Substituted Pyrrolidines
Scheme 5. Intramolecular aza-Michael additions of the silylated Mannich products.
Table 2. Variation of base, solvent, and temperature in base-promoted intramolecular aza-Michael additions of the silylated Mannich
product 5a (Scheme 5).
Entry
Base
Solvent
T [°C]
t [min]
Yield [%][a]
6a/7a[b]
1
2
3
4
5
6
7
8
9
KOtBu
KOtBu
NaOEt
NaH
THF
THF
DMF
DMF
THF
–78
room temp.
room temp.
room temp.
–78 to 0
–78
–78
–78
room temp.
30
5
5
10
190
40
40
180
30
86
46
59
68
82
80:20
11:89
20:80
25:75
75:25
Ͼ95:5
6:94
NaH
NaOEt[c]
KOtBu
NaOEt[d]
NaOEt
DMF/THF (2:1)
DMF/THF (2:1)
THF/EtOH (5:1)
THF/EtOH (10:1)
90
88
81[e]
63
89:11
[a] Yield of isolated product after flash column chromatography. [b] Determined by 1H NMR spectroscopy. [c] 1.5 equiv. [d] 10 equiv.
[e] 5a.
Treatment of the Mannich product 5a with KOtBu at
–78 °C furnished 6a with a diastereoselectivity of 80:20,
whereas at room temp., an excess of 7a was formed, albeit
in only 46% yield (Table 2, Entries 1 and 2). The yield of
7a was increased with use of NaOEt and NaH in DMF, but
the selectivities were still only 80:20 and 75:25, respectively
(Entries 3 and 4). Treatment of 5a with NaH in THF at low
temperatures led to an 82% yield of 6a in a dr of 75:25
(Entry 5). Finally, use of a DMF/THF solvent mixture at
–78 °C enabled us to perform highly diastereoselective aza-
Michael additions. The 2,5-trans-configured pyrrolidine 6a
was selectively formed with NaOEt as base in 90% yield
and with a diasteromeric ratio of Ͼ95:5 (Entry 6), whereas
treatment of 5a with KOtBu under the same conditions
gave an 88% yield of the 2,5-cis-configured pyrrolidine 7a
with a diastereoselectivity of 94:6 (Entry 7).
Table 3. trans-Diastereoselective aza-Michael reactions (Scheme 6).
Entry
Ar
Product
Yield [%][a]
trans/cis[b]
1
2
3
4
5
6
7
8
Ph
4-FC6H5
6a
6b
6c
6d
6e
6f
90
84
88
85
92
94
81
92
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
4-ClC6H5
4-MeOC6H5
4-CH3C6H5
3-CH3C6H5
2-CH3C6H5
2-furyl
6g
6h
[a] Yield of isolated product after flash column chromatography.
1
[b] Determined by H NMR spectroscopy.
These optimized conditions were subsequently applied to
the other Mannich products 5. With NaOEt as base in
DMF/THF (Scheme 6 and Table 3) the 2,5-trans-pyrrolid-
ines 6 were obtained in generally excellent yields ranging
between 81 and 94% and as single diastereomers according
Scheme 7. Synthesis of 2,5-cis-pyrrolidines 7a–h.
1
to H NMR analysis. With KOtBu as base (Scheme 7 and
Table 4), on the other hand, the 2,5-cis-pyrrolidines 7 were
prepared in 83–93% yields and with good diastereocontrol
of at least 90:10.
Table 4. cis-Diastereoselective aza-Michael reactions (Scheme 7).
Entry
Ar
Product
Yield [%][a]
cis/trans[b]
1
2
3
4
5
6
7
8
Ph
4-FC6H5
7a
7b
7c
7d
7e
7f
88
93
86
83
88
89
87
88
94:6
91:9
92:8
Ͼ95:5
Ͼ95:5
Ͼ95:5
90:10
Ͼ95:5
4-ClC6H5
4-MeOC6H5
4-CH3C6H5
3-CH3C6H5
2-CH3C6H5
2-furyl
7g
7h
[a] Yield of isolated product after flash column chromatography.
[b] Determined by H NMR spectroscopy.
1
Scheme 6. Synthesis of the 2,5-trans-pyrrolidines 6a–h.
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C. Enkisch, C. Schneider
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Scheme 8. Selective cleavage of the protecting groups.
Deprotection
conditions the thermodynamic product 7a was reisolated
in 78% yield and unchanged diastereomeric ratio (Table 5,
Entries 1 and 2). This suggests that 7a is indeed the thermo-
dynamically favored diastereomer. Upon treatment of 6a
and 7a with NaOEt in DMF/THF at –78 °C, the substrates
were isolated unchanged in almost quantitative yields (En-
tries 3 and 4). These findings imply that the deprotonation
of the ethyl ester does not proceed in the presence of Na-
OEt (Scheme 10). In contrast, KOtBu, being the stronger
base, is able to generate the ester enolate of 6a, thereby lead-
ing to a retro-aza-Michael reaction and accordingly to epi-
merization of the kinetically favored 2,5-trans-pyrrolidine
6a to the thermodynamically favored 2,5-cis-pyrrolidine 7a.
In contrast, the basicity of NaOEt appears to be insufficient
to deprotonate the ester. Hence the kinetically favored 2,5-
trans-pyrrolidine 6a, which is formed first, cannot be con-
verted into the 2,5-cis-pyrrolidine 7a when treated with Na-
OEt.
Selective cleavage of the protecting groups was achieved
for both diastereomers without affecting the diastereomeric
ratio (Scheme 8). The amino groups in 6a and 7a were Boc-
deprotected by treatment with ZnBr2, furnishing 8a and 8b
in 90% and 84% yields, respectively.[20] Cleavage of the silyl
ethers with Bu4NF proceeded smoothly, giving rise to 9a
and 9b in yields of 89% and 98%, respectively.[21] Both de-
protections proceeded without loss of diastereomeric purity.
Diastereoselectivities of the Aza-Michael Additions
DFT calculations performed on the desilylated methyl
esters 11 and 12 (Scheme 12, below) suggested that the 2,5-
cis-pyrrolidine is thermodynamically more stable than the
2,5-trans isomer by 13 kJmol–1, whereas the activation en-
ergy for the formation of the latter is 3 kJmol–1 less than
for the 2,5-cis-pyrrolidine.[22] This is in accordance with the
observation that 7a is obtained at higher temperatures
(Table 2, Entries 2–4), whereas the formation of 6a is fa-
vored at lower temperatures (Table 2, Entries 1 and 5). In
order to elucidate the influence of the base on the diastereo-
selectivity further, 6a and 7a were resubjected to the reac-
tion conditions described above (Scheme 9).
Table 5. Treatment of 2,5-trans- and 2,5-cis-pyrrolidines 6a and 7a
with base (Scheme 9).
Entry Substrate
Base
Product Yield [%][a] trans/cis[b]
1
2
3
4
6a
7a
6a
7a
1 equiv. KOtBu
1 equiv. KOtBu
1.5 equiv. NaOEt
1.5 equiv. NaOEt
7a
7a
6a
7a
64
78
95
94
6:94
Ͻ5:95
Ͼ95:5
6:94
Treatment of the kinetic product 6a with KOtBu in
DMF/THF at –78 °C furnished the epimerized product 7a
with high stereoselectivity, whereas under the same reaction [b] Determined by H NMR spectroscopy.
[a] Yield of isolated product after flash column chromatography.
1
Scheme 9. Examination of the epimerization of 2,5-trans- and 2,5-cis-pyrrolidines 6a and 7a under the reaction conditions.
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Stereodivergent Synthesis of Highly Substituted Pyrrolidines
Scheme 10. Equilibria in the intramolecular base-promoted aza-Michael additions.
The 2,5-trans selectivity observed with the use of KOtBu
in THF at –78 °C can be explained by solvation effects
(Table 2, Entry 1): DMF solvates the potassium ion much
better than THF thereby increasing the basicity of the
tBuO– anion. Thus, in THF the ion pairing of KOtBu is
more pronounced, and the basicity of the tBuO– anion is
attenuated relative to the case of the DMF/THF solvent
mixture. On the other hand, NaOEt is insoluble in THF,
and addition of ethanol leads to reisolation of the substrate
when the reaction is performed at –78 °C (Entry 8). Raising
the temperature to room temperature under otherwise iden-
tical reaction conditions results in the diastereoselective for-
mation of 6a (Entry 9). Here, protonation of the formed
ester enolate is accelerated by the addition of ethanol,
whereas the ethoxide anion is less basic, due to solvation
by ethanol. In summary, it can be concluded that the selec-
tivity of the intramolecular aza-Michael addition is gov-
erned on one hand by the temperature and on the other
by the actual basicity of the base, this being dependent on
solvation effects.
Scheme 11. Structural formula of Mannich product 10.
Figure 1. ORTEP[23] plot of the X-ray crystal structure of 10.
The assignment of the relative configuration of the pyr-
rolidines was derived from comparison of calculated con-
Assignment of the Absolute and Relative Configurations
By analogy with known Mannich products[18] and ac- formations[22] with NOE measurements. According to the
cording to the transition state[24] suggested for -proline- calculated structures of pyrrolidines 11 and 12, NOEs
catalyzed Mannich reactions the configuration of the Man- would be expected to occur between H3/H5 and H5/H2Јo
nich products 4 was assigned as (5S,6S). This was con- in 11, as well as between H3/H5Ј and H5Ј/H2Јo in 12
firmed by an X-ray crystal structure analysis of the 4-chlo- (Scheme 12, Figure 2, Table 6). Except for H3/H5 in the 2,5-
rophenyl derivative 10 (Scheme 11, Figure 1).
trans isomer, all contacts were observed in the NOESY
Eur. J. Org. Chem. 2009, 5549–5564
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C. Enkisch, C. Schneider
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Figure 2. Geometries of 11 and 12 from DFT calculations (tBu omitted for clarity).
spectra of 6a and 7a, so the (2S,3S,5S) configuration was and C3 were established through -proline-catalyzed Man-
assigned to 6a and the (2S,3S,5R) configuration was as- nich reactions, whereas the configuration at C5 was con-
signed to 7a. The assignment of the relative configuration trolled in base-promoted intramolecular aza-Michael ad-
was confirmed by X-ray crystal structure analysis of 12 ditions. In these ring closures, variation of the base permit-
(Figure 3).
ted the selective preparation either of 2,5-trans-pyrrolidines
6 or of 2,5-cis-pyrrolidines 7 with diastereomeric ratios be-
tween 90:10 and Ͼ95:5. Chemoselective deprotection of the
amino group and the side-chain hydroxy group proceeded
without loss of diastereomeric purity. The relative configu-
ration in 6 and 7 was determined by NOE measurements in
combination with conformational analysis by DFT meth-
ods. The assignments were confirmed by an X-ray crystal
structure analysis of 12. The absolute configuration was as-
signed by analogy with Mannich products known in the
literature, and was confirmed by an X-ray crystal structure
analysis of Mannich product 10. Both the DFT calculations
and the experimental results suggest that the 2,5-trans dia-
stereomers represent the kinetically favored products,
which, at higher temperatures or in the presence of a
stronger base, can isomerize to the thermodynamically fa-
vored 2,5-cis diastereomers.
Scheme 12. Structural formulae of 11 and 12.
Table 6. Calculated distances and results from NOESY spectra of
6a and 7a.
2,5-trans
Distance [Å] NOE
2,5-cis
Distance [Å] NOE
H3 to H5
H5 to H2Јo
2.767
2.836
no
yes
H3 to H5Ј
H5Ј to H2Јo
2.577
2.614
yes
yes
Experimental Section
General: All reactions were carried out with magnetic stirring under
nitrogen. Dry solvents were distilled from the indicated drying
agents: dichloromethane (CaH2), tetrahydrofuran (K), N,N-di-
methylformamide (CaH2). Acetonitrile and chloroform were ob-
tained from VWR in HPLC quality (HiPerSolvCHROM-
ANORM). Diethyl ether and petroleum ether (PE) for chromatog-
raphy were technical grade and distilled from KOH. Ethyl acetate
was distilled from CaCl2. All reactions were monitored by thin-
layer chromatography (TLC) on precoated silica gel plates (60 F254
,
Merck KGaA); spots were visualized by treatment with a solution
of vanillin (0.5 g), concd. acetic acid (10 mL), and concd. H2SO4
(5 mL) in methanol (90 mL), or with a solution of KMnO4 (3.0 g),
K2CO3 (20 g), and acetic acid (0.25 mL) in water (300 mL), or with
a solution of phosphomolybdic acid hydrate (1.0 g) in ethanol
(50 mL). Flash column chromatography was performed with
Merck silica gel 60 (230–400 mesh, 0.040–0.063 mm). -Proline was
racemized,[25] and imines 3[26] were prepared according to literature
procedures. All other chemicals were used as received from com-
Figure 3. ORTEP[23] plot of the X-ray crystal structure of 12.
Conclusions
A short and efficient reaction sequence for the stereo-
divergent synthesis of enantiomerically pure trisubstituted
pyrrolidines has been developed. The stereocenters at C2 mercial suppliers. 1H and 13C NMR spectra were recorded with
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Stereodivergent Synthesis of Highly Substituted Pyrrolidines
Varian Gemini 200 and 2000 (200 MHz), Varian Gemini 300 BB
(300 MHz), and Bruker Avance DRX 400 (400 MHz) spectrome-
ters. Chemical shifts are reported relative to tetramethylsilane as
internal standard or to the residual solvent signals [tetrachloroeth-
ane: δ(1H) = 6.00 ppm, chloroform: δ(13C) = 77.16 ppm]. Melting
points were determined with a Boetius heating table and are uncor-
rected. Elemental analyses were obtained from the microanalytical
laboratory of the Department of Chemistry at the University of
Leipzig. IR spectra were obtained with an FTIR spectrometer
(Genesis ATI, Mattson/Unicam). ESI mass spectra were recorded
with a Bruker APEX II FT-ICR (high resolution) and with a
Bruker ESQUIRE instrument. Optical rotations were measured
with a Schmidt & Haensch Polartronic D polarimeter. HPLC
analyses were performed with a JASCO MD-2010 plus instrument
with a chiral stationary-phase column (Chiralpak AD-H and Chi-
ralcel OD purchased from Daicel Chemical Industries, Ltd.).
retention times were compared with those for the enantioselective
runs.
Ethyl (2E,5S,6S)-6-[(tert-Butoxycarbonyl)amino]-5-(hydroxymeth-
yl)-6-phenylhex-2-enoate (4a): Yield: 502 mg, 82%, white solid. Rf
= 0.18 (Et2O/PE, 2:1). M.p. 120–123 °C. [α]2D2 = +13 (c = 1.1,
CHCl3). ee = 99%. Enantiomeric assay: Chiralpak AD-H, isocratic
(n-hexane/iPrOH, 90:10; flow 1.0 mLmin–1), λmax = 208 nm, t1
=
19.2 min, t2 = 22.4 min. 1H NMR (300 MHz, C2D2Cl4, 90 °C): δ =
3
1.3 (t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.5 [s, 9 H, C(CH3)3], 2.1–
3
2
2.3 (m, 4 H, 4-CH2, 5-CH, OH), 3.5 (dd, JH,H = 7.0, JH,H
=
11.0 Hz, 1 H, CH2OH), 3.6 (dd, 3JH,H = 4.0, 2JH,H = 11.0 Hz, 1 H,
CH2OH), 4.2 (q, JH,H = 7.0 Hz, 2 H, OCH2CH3), 5.0 (dd, JH,H
= 5.0, JH,H = 9.0 Hz, 6-CH), 5.2 (d, JH,H = 9.0 Hz, 1 H, NH),
5.9 (d, JH,H = 15.5 Hz, 1 H, 2-CH), 6.9 (dt, JH,H = 7.0, JH,H
3
3
3
3
3
3
3
=
15.5 Hz, 1 H, 3-CH), 7.1 (m, 3 H, ArH), 7.3 (m, 2 H, ArH) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 14.3 (OCH2CH3), 28.4
[C(CH3)3], 29.7 (C4), 45.6 (C5), 54.7 (C6), 60.4 (OCH2CH3), 62.5
(CH2OH), 80.1 [C(CH3)3], 123.1 (C2), 126.7 (C4Ј), 127.4 (C2Ј),
128.7 (C3Ј), 140.1 (C1Ј), 146.8 (C3), 156.3 (carbamate CO), 166.3
Ethyl (2E)-6-Oxohex-2-enoate (2):[19] 2,5-Dimethoxytetrahydro-
furan (93 mL, 0.72 mol) was added to HCl (1 , 360 mL), and the
mixture was stirred at room temp. for 10 min. Solid NaHCO3
(36.6 g, 0.43 mol) was added until pH = 6–6.5 was reached. The
aqueous phase was extracted with ethyl acetate (6ϫ350 mL), satu-
rated with NaCl, and again extracted with ethyl acetate
(3ϫ300 mL). The combined organic layers were dried with MgSO4
and filtered, and the solvent was evaporated in vacuo. Distillation
of the residue afforded succinaldehyde (36.71 g, 59%, b.p. 23 °C,
(C1) ppm. IR (KBr): ν = 3545 (OH), 3379 (NH), 3066, 3033, 2982,
˜
2937, 2907, 2878, 1703 (C=O), 1682 (C=O), 1652 (C=C), 1600
(C=C), 1580 (C=C), 1520 (C=O), 1500 (C=C), 1370, 1163, 758,
703 cm–1. UV/Vis (CH3CN): λmax (ε) = 207 (11783), 212 (12837),
217 (13752 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for C20H29NO5
[M + Na]+ 386.19379; found 386.19359.
56–61 mbar).
(36.71 g, 0.426 mol) in dry CH2Cl2 (1.11 L) was cooled in an ice
bath, and solution of ethoxycarbonyltriphenylphosphorane
A solution of freshly prepared succinaldehyde
Ethyl (2E,5S,6S)-6-[(tert-Butoxycarbonyl)amino]-6-(4-fluorophen-
yl)-5-(hydroxymethyl)hex-2-enoate (4b): Yield: 494 mg, 80%, white
solid. Rf = 0.15 (Et2O/PE 2:1). M.p. 147–148 °C. [α]2D2 = +18 (c =
1.09, CHCl3). ee = 99%. Enantiomeric assay: Chiralpak AD-H,
a
(37.08 g, 0.107 mol) in dry CH2Cl2 (370 mL) was added dropwise.
The reaction mixture was stirred at room temp. for 2 d. The solvent
was evaporated, and the residue was stirred in diethyl ether/pentane
(1:1, v/v; 3ϫ100 mL) for 10 min and filtered, the solids being
washed with a diethyl ether/pentane mixture (100 mL). The sol-
vents were evaporated, and the residue was distilled to remove un-
changed succinaldehyde (6.82 g, b.p. 50–60 °C, 15–20 mbar). The
residue was purified by flash column chromatography on silica gel
(1:20, w/w) with diethyl ether/petroleum ether [first 1:3, then 1:2
(v/v)] as eluent. The title compound was obtained as a colorless
liquid (6.83 g, 41%). Rf = 0.22 (Et2O/PE, 1:1). 1H NMR (200 MHz,
isocratic (n-hexane/iPrOH, 90:10; flow 1.0 mLmin–1), λmax
=
208 nm, t1 = 16.5 min, t2 = 21.7 min. 1H NMR (300 MHz,
3
C2D2Cl4, 90 °C): δ = 1.3 (t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.5
[s, 9 H, C(CH3)3], 2.1–2.3 (m, 4 H, 4-CH2, 5-CH, OH), 3.5 (dd,
2
3
3JH,H = 7.0, JH,H = 11.0 Hz, 1 H, CH2OH), 3.6 (dd, JH,H = 4.0,
2JH,H = 11.0 Hz, 1 H, CH2OH), 4.2 (q, 3JH,H = 7.0 Hz, OCH2CH3),
5.0 (dd, JH,H = 4.5, JH,H = 9.0 Hz, 1 H, 6-CH), 5.2 (d, JH,H
3
3
3
=
9.0 Hz, 1 H, NH), 7.1 (mc, 2 H, ArH), 7.3 (m, 2 H, ArH) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 14.3 (OCH2CH3), 28.4
[C(CH3)3], 29.9 (C4), 45.4 (C5), 54.5 (C6), 60.5 (OCH2CH3), 62.5
(CH2OH), 80.3 [C(CH3)3], 115.5 (2JC,F = 21.0 Hz, C3Ј, C5Ј), 123.3
(C2), 128.4 (3JC,F = 7.5 Hz, C2Ј, C6Ј), 135.9 (C1Ј), 146.5 (C3),
156.1 (carbamate CO), 162.1 (1JC,F = 244 Hz, C4Ј), 166.3 (C1)
3
CDCl3, 29 °C): δ = 1.3 (t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 2.5–
3
2.7 (m, 4 H, 4-CH2, 5-CH2), 4.2 (q, JH,H = 7.0 Hz, 2 H,
4
3
OCH2CH3), 5.9 (dt, JH,H = 1.5, JH,H = 15.5 Hz, 1 H, 2-CH), 6.9
3
3
(dt, JH,H = 6.5, JH,H = 15.5 Hz, 1 H, 3-CH), 9.8 (s, 1 H, CHO)
ppm. IR (KBr): ν = 3503 (OH), 3381 (NH), 3010, 2981, 2939, 2907,
˜
ppm.
1698 (C=O), 1681 (C=O), 1653 (C=C), 1606 (C=C), 1517 (C=O),
1510 (C=C), 1368, 1292, 1226, 1177, 1159, 841 cm–1. UV/Vis
(CH3CN): λmax (ε) = 205 (13096), 210 (15793), 263 (444), 270
(309 mol–1 dm3 cm–1) nm. MS (ESI): m/z = 404 [M + Na]+, 785 [2
M + Na]+. C20H28FNO5 (381.44): calcd. C 62.98, H 7.40, N 3.67;
found C 62.83, H 7.46, N 3.51.
General Procedure for the L-Proline-Catalyzed Mannich Reactions:
An imine 3 (1.0 equiv.) was added to a solution of the aldehyde 2
(0.1 , 1.0 equiv.) in acetonitrile. The mixture was cooled in an ice
bath under argon. -Proline (0.2 equiv.) was added. After 6–7 h, a
further solution of imine (1.0 equiv.) in acetonitrile (1 ) was
added. After consumption of the aldehyde as monitored by TLC
(after 24–28 h reaction time), the reaction mixture was transferred
at 0 °C to a flask containing a freshly prepared solution of NaBH4
(3.0 equiv.) and acetic acid (1.35 equiv.) in ethyl acetate (0.3  with
respect to NaBH4). After 5 min at 0 °C, an equal volume of satu-
rated NH4Cl solution was added. The aqueous phase was extracted
three times with ethyl acetate. The combined organic layers were
dried with MgSO4 and filtered, and the solvents were evaporated
in vacuo. The residue was dissolved in a small amount of ethyl
acetate and ethanol, adsorbed on silica gel, and purified by flash
column chromatography on silica gel (1:50, w/w) with diethyl ether/
petroleum ether as eluent. For purposes of authentication, the race-
mic products were prepared by use of -proline, and the HPLC
Ethyl
(2E,5S,6S)-6-[(tert-Butoxycarbonyl)amino]-6-(4-chloro-
phenyl)-5-(hydroxymethyl)hex-2-enoate (4c): Yield: 391 mg, 83%,
white solid. Rf = 0.l6 (Et2O/PE, 2:1). M.p. 130–131 °C. [α]2D2 = +13
(c = 1.04, CHCl3). ee = 99%. Enantiomeric assay: Chiralpak AD-
H, isocratic (n-hexane/iPrOH, 90:10; flow 1.0 mLmin–1), λmax
=
204 nm, t1 = 17.2 min, t2 = 23.2 min. 1H NMR (300 MHz,
3
C2D2Cl4, 90 °C): δ = 1.3 (t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.5
[s, 9 H, C(CH3)3], 2.1–2.3 (m, 4 H, 4-CH2, 5-CH, OH), 3.5–3.6 (m,
3
2 H, CH2OH), 4.2 (q, JH,H = 7.0 Hz, 2 H, OCH2CH3), 5.0 (dd,
3
3
3JH,H = 4.5, JH,H = 9.0 Hz, 1 H, 6-CH), 5.2 (d, JH,H = 9.0 Hz, 1
3
3
H, NH), 5.9 (d, JH,H = 15.5 Hz, 1 H, 2-CH), 6.9 (dt, JH,H = 7.5,
3JH,H = 15.5 Hz, 1 H, 3-CH), 7.3 (br. d, 3JH,H = 8.5 Hz, 2 H, ArH),
7.4 (br. d, JH,H = 8.5 Hz, 2 H, ArH) ppm. 13C NMR (100 MHz,
3
Eur. J. Org. Chem. 2009, 5549–5564
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5555

C. Enkisch, C. Schneider
CDCl3, 25 °C): δ = 14.3 (OCH2CH3), 28.4 [C(CH3)3], 30.0 (C4), CHCl3). ee = 82%. Enantiomeric assay: Chiralcel OD, isocratic
FULL PAPER
45.2 (C5), 54.6 (C6), 60.5 (OCH2CH3), 62.4 (CH2OH), 80.4 (n-hexane/iPrOH, 90:10; flow 0.5 mLmin–1), λmax = 212 nm, t1
=
[C(CH3)3], 122.3 (C2), 128.3, 128.8 (C2Ј, C3Ј, C5Ј, C6Ј), 133.2 14.4 min, t2 = 15.9 min. 1H NMR (300 MHz, C2D2Cl4, 90 °C): δ =
3
(C4Ј), 138.7 (C1Ј), 146.4 (C3), 156.1 (carbamate CO), 166.3 (C1)
1.3 (t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.5 [s, 9 H, C(CH3)3], 2.1–
3
ppm. IR (KBr): ν = 3495 (OH), 3370 (NH), 2980, 2935, 1720 2.4 (m, 4 H, 4-CH2, 5-CH, OH), 2.4 (s, 3 H, CH3), 3.5 (dd, JH,H
˜
2
3
2
(C=O), 1700 (C=O), 1681, 1651 (C=C), 1520 (C=O), 1493 (C=C),
= 7.0, JH,H = 11.5 Hz, 1 H, CH2OH), 3.6 (dd, JH,H = 4.5, JH,H
1445, 1368, 1287, 1251, 1169, 1092, 1040, 1014 cm–1. UV/Vis = 11.5 Hz, 1 H, CH2OH), 4.2 (q, 3JH,H = 7.0 Hz, 2 H, OCH2CH3),
(CH3CN): λmax (ε) = 217 (17838 mol–1 dm3 cm–1) nm. MS (ESI):
m/z = 398 [M + H]+, 420 [M + Na]+. C20H28ClNO5 (397.89): calcd.
C 60.37, H 7.09, N 3.52; found C 60.24, H 7.16, N 3.35.
5.0 (dd, JH,H = 5.0, JH,H = 9.0 Hz, 1 H, 6-CH), 5.1 (d, JH,H =
3
3
3
3
9.0 Hz, 1 H, NH), 5.8 (d, JH,H = 15.5 Hz, 1 H, 2-CH), 6.9 (dt,
3JH,H = 7.5, JH,H = 15.5 Hz, 1 H, 3-CH), 7.1–7.2 (m, 3 H, ArH),
3
7.3 (t, JH,H = 8.0 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz,
3
Ethyl (2E,5S,6S)-6-[(tert-Butoxycarbonyl)amino]-5-(hydroxymeth-
yl)-6-(4-methoxyphenyl)hex-2-enoate (4d): Yield: 356 mg, 58%,
white solid. Rf = 0.15 (Et2O/PE, 2:1). M.p. 110–112 °C. [α]2D2 = +8
(c = 1.26, CHCl3). ee = 99%. Enantiomeric assay: Chiralpak AD-
CDCl3, 25 °C): δ = 14.3 (OCH2CH3), 21.6 (CH3), 28.4 [C(CH3)3],
29.7 (C4), 45.8 (C5), 54.5 (C6), 60.4 (OCH2CH3), 62.6 (CH2OH),
80.2 [C(CH3)3], 123.0 (C2), 123.6 (C6Ј), 127.4 (C4Ј), 128.1 (C5Ј),
128.6 (C2Ј), 138.3 (C3Ј), 140.0 (C1Ј), 146.9 (C3), 156.4 (carbamate
H, isocratic (n-hexane/iPrOH, 90:10; flow 1.0 mLmin–1), λmax
=
CO), 166.3 (C1) ppm. IR (KBr): ν = 3558 (OH), 3384 (NH), 2977,
˜
204 nm, t1 = 23.6 min, t2 = 31.0 min. 1H NMR (300 MHz,
2910, 1708 (C=O), 1686 (C=O), 1651 (C=C), 1608 (C=C), 1519
(C=C), 1368, 1212, 1161 cm–1. UV/Vis (CH3CN): λmax (ε) = 215
(20920 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for C21H31NO5 [M
+ Na]+ 400.20944; found 400.20913.
3
C2D2Cl4, 90 °C): δ = 1.3 (t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.5
[s, 9 H, C(CH3)3], 2.1–2.3 (m, 4 H, 4-CH2, 5-CH, OH), 3.5 (dd,
2
3
3JH,H = 7.0, JH,H = 11.5 Hz, 1 H, CH2OH), 3.6 (dd, JH,H = 4.5,
2JH,H = 11.5 Hz, 1 H, CH2OH), 3.9 (s, 3 H, OCH3), 4.2 (q, JH,H
= 7.0 Hz, 2 H, OCH2CH3), 4.9 (dd, JH,H = 5.0, JH,H = 9.0 Hz, 1
H, 6-CH), 5.1 (d, JH,H = 9.0 Hz, 1 H, NH), 5.9 (d, JH,H
15.5 Hz, 1 H, 2-CH), 6.5–7.0 (m, 1 H, 3-CH), 6.9 (br. d, JH,H
3
3
3
Ethyl (2E,5S,6S)-6-[(tert-Butoxycarbonyl)amino]-5-(hydroxymeth-
yl)-6-(2-methylphenyl)hex-2-enoate (4g): Yield: 408 mg, 97%, vis-
cous oil. Rf = 0.22 (Et2O/PE, 2:1). [α]2D2 = –17 (c = 1.09, CHCl3).
ee = 99%. Enantiomeric assay: Chiralpak AD-H, isocratic (n-hex-
3
3
=
=
3
8.5 Hz, 2 H, ArH), 7.2 (br. d, 3JH,H = 8.5 Hz, 2 H, ArH) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 14.3 (OCH2CH3), 28.4
[C(CH3)3], 29.9 (C4), 45.5 (C5), 54.3 (C6), 55.3 (OCH3), 60.3
(OCH2CH3), 62.5 (CH2OH), 80.0 [C(CH3)3], 114.0 (C3Ј), 123.0
(C2), 127.8 (C2Ј), 132.1 (C1Ј), 146.9 (C3), 156.2 (carbamate CO),
ane/iPrOH, 90:10; flow 1.0 mLmin–1), λmax = 208 nm, t1
=
18.9 min, t2 = 21.3 min. 1H NMR (300 MHz, C2D2Cl4, 90 °C): δ =
3
1.3 (t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.5 [s, 9 H, C(CH3)3], 2.1–
3
2.5 (m, 4 H, 4-CH2, 5-CH, OH), 2.5 (s, 3 H, CH3), 3.5 (d, JH,H
5.5 Hz, 2 H, CH2OH), 4.2 (q, JH,H = 7.0 Hz, 2 H, OCH2CH3),
5.0 (d, JH,H = 9.0 Hz, 1 H, NH), 5.2 (dd, JH,H = 6.0, JH,H
=
3
158.8 (C4Ј), 166.4 (C1) ppm. IR (KBr): ν = 3484 (OH), 3374 (NH),
˜
3
3
3
=
3068, 2977, 2935, 2835, 1702 (C=O), 1681 (C=O), 1651 (C=C),
1614 (C=C), 1586 (C=C), 1514 (C=C, C=O), 1369, 1297, 1251,
1206, 1174, 1035, 1021, 835, 816 cm–1. UV/Vis (CH3CN): λmax (ε)
= 208 (17657), 211 (17653), 217 (17382), 221 (17106), 274 (1651),
282 (1342 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for [M + Na]+
416.20436; found 416.20399. HRMS-ESI: calcd. for [2 M + Na]+
809.41950; found 809.41973.
3
9.0 Hz,1 H, 6-CH), 5.9 (d, JH,H = 15.5 Hz, 1 H, 2-CH), 6.9 (mc,
1 H, 3-CH), 6.9–7.3 (m, 4 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 14.3 (OCH2CH3), 19.5 (CH3), 28.4 [C(CH3)3],
29.3 (C4), 44.9 (C5), 50.5 (C6), 60.3 (OCH2CH3), 62.5 (CH2OH),
80.1 [C(CH3)3], 122.9 (C2), 125.5 (C5Ј), 126.1 (C4Ј), 127.3 (C6Ј),
131.2 (C3Ј), 135.7 (C2Ј), 138.8 (C1Ј), 147.2 (C3), 156.4 (carbamate
CO), 166.4 (C1) ppm. IR (film): ν = 3450 (OH), 3370 (NH), 2979,
˜
Ethyl (2E,5S,6S)-6-[(tert-Butoxycarbonyl)amino]-5-(hydroxymeth-
yl)-6-(4-methylphenyl)hex-2-enoate (4e): Yield: 339 mg, 76%, white
solid. Rf = 0.18 (Et2O/PE, 2:1). M.p. 121–122 °C. [α]2D2 = +10 (c =
1.0, CHCl3). ee = 99%. Enantiomeric assay: Chiralpak AD-H, iso-
cratic (n-hexane/iPrOH, 90:10; flow 1.0 mLmin–1), λmax = 212 nm,
t1 = 16.7 min, t2 = 19.8 min. 1H NMR (300 MHz, C2D2Cl4, 90 °C):
2931, 1725 (C=O), 1698 (C=O), 1652 (C=C), 1600 (C=C), 1493
(C=C), 1385, 1367, 1169, 1044, 787, 762 cm–1. UV/Vis (CH3CN):
λmax (ε) = 202 (14995), 211 (19191), 216 (19551 mol–1 dm3 cm–1)
nm. HRMS-ESI: calcd. for C21H31NO5 [M + Na]+ 400.20944;
found 400.20941.
Ethyl (2E,5S,6S)-6-[(tert-Butoxycarbonyl)amino]-6-(2-furyl)-5-(hy-
droxymethyl)hex-2-enoate (4h): Yield: 372 mg, 63%, white solid. Rf
= 0.17 (Et2O/PE, 2:1). M.p. 60–64 °C. [α]2D2 = +7 (c = 1.13, CHCl3).
ee = 98%. Enantiomeric assay: Chiralpak AD-H, isocratic (n-hex-
ane/iPrOH, 95:5; flow 0.5 mLmin–1), λmax = 212 nm, t1 = 91.3 min,
t2 = 96.6 min. 1H NMR (300 MHz, C2D2Cl4, 90 °C): δ = 1.3 (t,
3JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.5 [s, 9 H, C(CH3)3], 2.1–2.3 (m,
3
δ = 1.3 (t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.5 [s, 9 H, C(CH3)3],
2.1–2.3 (m, 4 H, 4-CH2, 5-CH, OH), 2.4 (s, 3 H, CH3), 3.5 (dd,
2
3
3JH,H = 7.0, JH,H = 11.5 Hz, 1 H, CH2OH), 3.6 (dd, JH,H = 4.5,
2JH,H = 11.5 Hz, 1 H, CH2OH), 4.2 (q, JH,H = 7.0 Hz, 2 H,
3
3
3
OCH2CH3), 5.0 (dd, JH,H = 5.0, JH,H = 9.0 Hz, 1 H, 6-CH), 5.1
(d, 3JH,H = 9.0 Hz, 1 H, NH), 5.8 (d, 3JH,H = 15.5 Hz, 1 H, 2-CH),
6.9 (mc, 1 H, 3-CH), 7.2 (m, 4 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 14.3 (OCH2CH3), 21.1 (CH3), 28.4 [C(CH3)3],
29.7 (C4), 45.6 (C5), 54.4 (C6), 60.3 (OCH2CH3), 62.6 (CH2OH),
80.1 [C(CH3)3], 123.0 (C2), 126.6 (C2Ј), 129.4 (C3Ј), 137.0 (C1Ј,
C4Ј), 146.9 (C3), 156.3 (carbamate CO), 166.3 (C1) ppm. IR (KBr):
3
2
3 H, 4-CH2, 5-CH), 3.5 (dd, JH,H = 7.5, JH,H = 11.5 Hz, 1 H,
CH2OH), 3.6 (dd, 3JH,H = 4.5, 2JH,H = 11.5 Hz, 1 H, CH2OH), 4.2
(q, JH,H = 7.0 Hz, 2 H, OCH2CH3), 5.1 (m, 2 H, 6-CH, NH), 5.9
(dt, JH,H = 1.5 H, JH,H = 15.5 Hz, 1 H, 2-CH), 6.2 (d, JH,H
3.0 Hz, 1 H, 3-furyl-H), 6.4 (dd, JH,H = 2.0, JH,H = 3.0 Hz, 1 H,
3
4
3
3
=
3
3
ν = 3500 (OH), 3379 (NH), 2980, 2934, 1717 (C=O), 1681 (C=O),
˜
3
3
4-furyl-H), 6.9 (dt, JH,H = 7.0, JH,H = 15.5 Hz, 1 H, 3-CH), 7.4
1651 (C=C), 1519 (C=C), 1368, 1251, 1172 cm–1. UV/Vis
(dd, JH,H = 1.0, JH,H = 2.0 Hz, 1 H, 5-furyl-H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 14.3 (OCH2CH3), 28.4 [C(CH3)3],
29.8 (C4), 45.0 (C5), 49.2 (C6), 60.3 (OCH2CH3), 62.5 (CH2OH),
80.6 [C(CH3)3], 106.6 (C3Ј), 110.5 (C4Ј), 122.9 (C2), 141.9 (C5Ј),
146.5 (C3), 153.0 (C2Ј), 156.5 (carbamate CO), 166.3 (C1) ppm.
4
3
(CH3CN): λmax (ε)
=
211 (14427), 217 (14321), 264
(254 mol–1 dm3 cm–1) nm. MS (ESI): m/z = 400 [M + Na]+, 777 [2
M + Na]+. C21H31NO5 (377.47): calcd. C 66.82, H 8.28, N 3.71;
found C 66.68, H 8.27, N 3.58.
Ethyl (2E,5S,6S)-6-[(tert-Butoxycarbonyl)amino]-5-(hydroxymeth- IR (KBr): ν = 3537 (OH), 3367 (NH), 2985, 2936, 1708 (C=O),
˜
yl)-6-(3-methylphenyl)hex-2-enoate (4f): Yield: 268 mg, 44%, white 1684 (C=O), 1652 (C=C), 1600 (C=C), 1518, 1367, 1322, 1266,
solid. Rf = 0.21 (Et2O/PE, 2:1). M.p. 57–58 °C. [α]2D2 = +7 (c = 1.46,
1252, 1210, 1161, 1010 cm–1. UV/Vis (CH3CN): λmax (ε) = 215
5556
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5549–5564

Stereodivergent Synthesis of Highly Substituted Pyrrolidines
(15493 mol–1 dm3 cm–1) nm. MS (ESI): m/z = 376 [M + Na]+, 729 394 mg, 99%, viscous oil. Rf = 0.50 (Et2O/PE, 2:1). [α]2D3 = –2 (c =
1
[2 M + Na]+. C18H27NO6 (353.41): calcd. C 61.17, H 7.70, N 3.96;
found C 60.81, H 7.72, N 3.89.
6.38, CHCl3). H NMR (300 MHz, C2D2Cl4, 90 °C): δ = 0.1 (s, 3
H, SiCH3), 0.1 (s, 3 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3 (t, 3JH,H
= 7.0 Hz, 3 H, OCH2CH3), 1.4 [s, 9 H, OC(CH3)3], 2.1–2.3 (m, 3
General Procedure for the Silylation of the Mannich Products: tert-
Butyldimethylsilyl chloride (1.5 equiv.), imidazole (2.0 equiv.), and
4-(dimethylamino)pyridine (0.19 equiv.) were added under nitrogen
to a solution of the Mannich product 4 in dry dichloromethane
(0.2 , 1.0 equiv.). The reaction mixture was stirred at room temp.
for 1–1.5 h. Water was added, and the aqueous phase was extracted
three times with ethyl acetate. The combined organic layers were
dried with MgSO4 and filtered, and the solvents were evaporated
in vacuo. The residue was dissolved in a small amount of diethyl
ether, adsorbed on silica gel, and purified by flash column
chromatography on silica gel (1:50, w/w) with mixtures of diethyl
ether/petroleum ether as eluent.
3
H, 4-CH2, 5-CH), 3.5 (d, JH,H = 5.0 Hz, 2 H, CH2OTBS), 4.2 (q,
3JH,H = 7.0 Hz, 2 H, OCH2CH3), 4.8 (dd, JH,H = 5.0, JH,H
=
3
3
3
8.0 Hz, 1 H, 6-CH), 5.7 (br., 1 H, NH), 5.9 (d, JH,H = 15.5 Hz, 1
3
3
H, 2-CH), 6.9 (dt, JH,H = 7.0, JH,H = 15.5 Hz, 1 H, 3-CH), 7.2
(br. d, 2 H, ArH), 7.4 (m, 2 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = –5.6 (SiCH3), 14.4 (OCH2CH3), 18.1 [SiC-
(CH3)3], 26.0 [SiC(CH3)3], 28.4 [OC(CH3)3], 30.9 (C4), 44.3 (C5),
57.0 (C6), 60.4 (OCH2CH3), 63.1 (CH2OTBS), 79.3 [OC(CH3)3],
123.5 (C2), 128.5, 128.7 (C2Ј, C3Ј, C5Ј, C6Ј), 133.1 (C4Ј), 138.8
(C1Ј), 146.4 (C3), 155.2 (carbamate CO), 166.2 (ester CO) ppm. IR
(film): ν = 3368, 3270, 3132, 2955, 2930, 2858, 1720 (C=O), 1699
˜
(C=O), 1654 (C=C), 1597 (C=C), 1578 (C=C), 1492 (C=C), 1385,
1367, 1258, 1170, 1092, 837, 787 cm–1. UV/Vis (CH3CN): λmax (ε)
Ethyl (2E,5S,6S)-6-[(tert-Butoxycarbonyl)amino]-5-{[(tert-butyldi-
methylsilyl)oxy]methyl}-6-phenylhex-2-enoate (5a): Yield: 2.76 g,
96%, viscous oil. Rf = 0.61 (Et2O/PE, 2:1). [α]2D2 = –8 (c = 1.32,
CHCl3). 1H NMR (300 MHz, C2D2Cl4, 90 °C): δ = 0.1 (s, 3 H,
=
220 (36409 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for
C26H42NO5Si [M + Na]+ 534.24130; found 534.24145.
Ethyl (2E,5S,6S)-6-[(tert-Butoxycarbonyl)amino]-5-{[(tert-butyldi-
3
SiCH3), 0.1 (s, 3 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3 (t, JH,H
methylsilyl)oxy]methyl}-6-(4-methoxyphenyl)hex-2-enoate
(5d):
= 7.0 Hz, 3 H, OCH2CH3), 1.4 [s, 9 H, OC(CH3)3], 2.1–2.4 (m, 3
Yield: 369 mg, 88%, viscous oil. Rf = 0.43 (Et2O/PE, 2:1). [α]2D3
=
3
2
H, 4-CH2, 5-CH), 3.5 (dd, JH,H = 4.0, JH,H = 10.5 Hz, 1 H,
1
–8 (c = 1.30, CHCl3). H NMR (400 MHz, C2D2Cl4, 90 °C): δ =
0.1 (s, 3 H, SiCH3), 0.1 (s, 3 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3],
1.3 (t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.4 [s, 9 H, OC(CH3)3],
2.1–2.3 (m, 3 H, 4-CH2, 5-CH), 3.5 (dd, JH,H = 4.0, JH,H
10.5 Hz, 1 H, CH2OTBS), 3.5 (dd, JH,H = 6.0, JH,H = 10.5 Hz, 1
H, CH2OTBS), 3.9 (s, 3 H, OCH3), 4.2 (q, JH,H = 7.0 Hz,
OCH2CH3), 4.7 (dd, JH,H = 5.5, JH,H = 8.5 Hz, 1 H, 6-CH), 5.6
(br., 1 H, NH), 5.9 (d, JH,H = 15.5 Hz, 1 H, 2-CH), 6.9 (br. d,
CH2OH), 3.5 (dd, 3JH,H = 6.0, 2JH,H = 10.5 Hz, 1 H, CH2OH), 4.2
(q, JH,H = 7.0 Hz, 2 H, OCH2CH3), 4.8 (dd, JH,H = 5.0, JH,H
8.5 Hz, 1 H, 6-CH), 5.7 (br., 1 H, NH), 5.9 (d, JH,H = 15.5 Hz, 1
H, 2-CH), 6.9 (dt, JH,H = 7.0, JH,H = 15.5 Hz, 1 H, 3-CH), 7.3–
7.4 (m, 5 H, ArH) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ =
–5.6 (SiCH3), 14.4 (OCH2CH3), 18.2 [C(CH3)3Si], 26.0 [SiC-
(CH3)3], 28.5 [OC(CH3)3], 31.1 (C4), 44.7 (C5), 57.3 (C6), 60.3
(OCH2CH3), 63.0 (CH2OTBS), 79.2 [OC(CH3)3], 123.3 (C2), 127.3
(Car), 128.4 (Car), 140.2 (q Car), 146.9 (C3), 155.3 (carbamate CO),
3
3
3
=
3
3
3
2
=
3
3
3
2
3
3
3
3
3JH,H = 8.5 Hz, 2 H, ArH), 6.9 (dt, JH,H = 7.0, JH,H = 15.5 Hz,
1 H, 3-CH), 7.2 (br. d, 3JH,H = 8.5 Hz, 2 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = –5.6 (SiCH3), 14.4 (OCH2CH3), 18.2
[SiC(CH3)3], 26.0 [SiC(CH3)3], 28.5 [OC(CH3)3], 31.2 (C4), 44.7
(C5), 55.3 (OCH3), 56.8 (C6), 60.4 (OCH2CH3), 63.1 (CH2OTBS),
79.1 [OC(CH3)3], 113.8 (C3Ј, C5Ј), 123.3 (C2), 128.4 (C2Ј, C6Ј),
132.3 (C1Ј), 147.0 (C3), 155.3 (carbamate CO), 158.8 (C4Ј), 166.4
3
3
166.4 (C1) ppm. IR (film): ν = 3367 (NH), 3064, 3031, 2955, 2930,
˜
2858, 1699 (C=O), 1653 (C=O), 1603 (C=C), 1496 (C=C), 1384,
1365, 1257, 1170, 1112, 1044, 837, 777, 757 cm–1. UV/Vis
(CH3CN): λmax (ε) = 210 (19731 mol–1 dm3 cm–1) nm. MS (ESI):
m/z = 500 [M + Na]+, 977 [2 M + Na]+. C26H43NO5Si (477.77):
calcd. C 65.37, H 9.07, N 2.93; found C 65.61, H 9.40, N 3.00.
(ester CO) ppm. IR (film): ν = 3370, 3130, 2955, 2930, 2858, 1719
˜
Ethyl (2E,5S,6S)-6-[(tert-Butoxycarbonyl)amino]-5-{[(tert-butyldi-
methylsilyl)oxy]methyl}-6-(4-fluorophenyl)hex-2-enoate (5b): Yield:
533 mg, 99%, viscous oil. Rf = 0.17 (Et2O/PE, 1:2). [α]2D2 = –7 (c =
(C=O), 1700 (C=O), 1654 (C=C), 1613 (C=C), 1586 (C=C), 1513
(C=O), 1500 (C=C), 1385, 1250, 1173, 836, 787 cm–1. UV/Vis
(CH3CN): λmax (ε)
=
202 (21187), 213 (20725), 275
1
(2034 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for C27H45NO6Si [M
+ Na]+ 530.29084; found 530.290862.
1.19, CHCl3). H NMR (300 MHz, C2D2Cl4, 90 °C): δ = 0.1 (s, 3
H, SiCH3), 0.1 (s, 3 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3 (t, 3JH,H
= 7.0 Hz, 3 H, OCH2CH3), 1.4 [s, 9 H, OC(CH3)3], 2.1–2.2 (m, 3
Ethyl (2E,5S,6S)-6-[(tert-Butoxycarbonyl)amino]-5-{[(tert-butyldi-
methylsilyl)oxy]methyl}-6-(4-methylphenyl)hex-2-enoate (5e): Yield:
364 mg, quant., viscous oil. Rf = 0.65 (Et2O/PE, 2:1). [α]2D3 = –7 (c
3
H, 4-CH2, 5-CH), 3.5 (d, JH,H = 5.0 Hz, 2 H, CH2OTBS), 4.2 (q,
3
3
3JH,H = 7.0 Hz, 2 H, OCH2CH3), 4.8 (dd, JH,H = 5.0, JH,H
=
3
8.0 Hz, 1 H, 6-CH), 5.7 (br., 1 H, NH), 5.9 (d, JH,H = 15.5 Hz, 1
H, 2-CH), 6.9 (dt, JH,H = 7.0, JH,H = 15.5 Hz, 1 H, 3-CH), 7.1
1
= 1.21, CHCl3). H NMR (400 MHz, C2D2Cl4, 90 °C): δ = 0.1 (s,
3
3
3 H, SiCH3), 0.1 (s, 3 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3 (t,
3
3
(br. t, JH,H = JH,F = 8.5 Hz, 2 H, 3Ј-CH, 5Ј-CH), 7.3 (m, 2 H,
2Ј-CH, 6Ј-CH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = –5.6
(SiCH3), 14.3 (OCH2CH3), 18.1 [SiC(CH3)3], 26.0 [SiC(CH3)3],
28.4 [OC(CH3)3], 31.0 (C4), 44.5 (C5), 56.8 (C6), 60.4 (OCH2CH3),
63.0 (CH2OTBS), 79.3 [OC(CH3)3], 115.2 (2JC,F = 21.5 Hz, C3Ј,
C5Ј), 123.5 (C2), 128.8 (3JC,F = 8.0 Hz, C2Ј, C6Ј), 136.0 (C1Ј),
146.5 (C3), 155.2 (carbamate CO), 162.0 (1JC,F = 245.0 Hz, C4Ј),
3JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.4 [s, 9 H, OC(CH3)3], 2.1–2.3
3
(m, 3 H, 4-CH2, 5-CH), 2.4 (s, 3 H, CH3), 3.5 (dd, JH,H = 4.0,
3
2
2JH,H = 10.0 Hz, 1 H, CH2OTBS), 3.5 (dd, JH,H = 6.0, JH,H
=
10.0 Hz, 1 H, CH2OTBS), 4.2 (q, 3JH,H = 7.0 Hz, 2 H, OCH2CH3),
4.8 (dd, JH,H = 5.5, JH,H = 8.0 Hz, 1 H, 6-CH), 5.6 (br., 1 H,
3
3
3
3
NH), 5.9 (d, JH,H = 15.5 Hz, 1 H, 2-CH), 6.9 (dt, JH,H = 7.0,
3JH,H = 15.5 Hz, 1 H, 3-CH), 7.2 (m, 4 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = –5.6 (SiCH3), 14.4 (OCH2CH3), 18.2
[SiC(CH3)3], 21.2 (CH3), 26.0 [SiC(CH3)3], 28.5 [OC(CH3)3], 31.2
(C4), 44.7 (C5), 57.1 (C6), 60.3 (OCH2CH3), 63.1 (CH2OTBS), 79.0
[OC(CH3)3], 123.3 (C2), 127.3 (C2Ј, C6Ј), 129.1 (C3Ј, C5Ј), 136.8,
137.2 (q Car), 147.0 (C3), 155.3 (carbamate CO), 166.4 (ester CO)
166.3 (C1) ppm. IR (film): ν = 3368, 3269 (NH), 3130, 2956, 2930,
˜
2858, 1720 (C=O), 1700 (C=O), 1655 (C=C), 1606 (C=C), 1510
(C=C), 1385, 1367, 1258, 1225, 1172, 1113, 1144, 838, 787 cm–1.
UV/Vis (CH3CN): λmax (ε) = 208 (11508 mol–1 dm3 cm–1) nm. MS
(ESI): m/z = 518 [M + Na]+, 1013 [2 M + Na]+. C26H42FNO5Si
(495.70): calcd. C 63.00, H 8.54; found C 62.81, H 8.72.
ppm. IR (film): ν = 3368, 3271, 2956, 2929, 2858, 2739, 1720
˜
Ethyl (2E,5S,6S)-6-[(tert-Butoxycarbonyl)amino]-5-{[(tert-butyldi-
methylsilyl)oxy]methyl}-6-(4-chlorophenyl)hex-2-enoate (5c): Yield:
(C=O), 1700 (C=O), 1654 (C=C), 1620 (C=C), 1575 (C=C), 1513
(C=O), 1500 (C=C), 1385, 1367, 1258, 1171, 1111, 1045, 837,
Eur. J. Org. Chem. 2009, 5549–5564
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5557

C. Enkisch, C. Schneider
FULL PAPER
786 cm–1. UV/Vis (CH3CN): λmax (ε)
=
201 (22350), 208 (SiCH3), 14.4 (OCH2CH3), 18.2 [SiC(CH3)3], 25.9 [SiC(CH3)3],
(21476 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for C27H45NO5Si
[M + H]+ 492.31398; found 492.31410.
28.4 [OC(CH3)3], 31.3 (C4), 43.9 (C5), 51.0 (C6), 60.3 (OCH2CH3),
63.4 (CH2OTBS), 79.4 [OC(CH3)3], 107.2 (C3Ј), 110.2 (C4Ј), 123.3
(C2), 141.7 (C5Ј), 146.7 (C3), 153.3 (C2Ј), 155.2 (carbamate CO),
Ethyl (2E,5S,6S)-6-[(tert-Butoxycarbonyl)amino]-5-{[(tert-butyldi-
methylsilyl)oxy]methyl}-6-(3-methylphenyl)hex-2-enoate (5f): Yield:
246 mg, 84%, viscous oil. Rf = 0.67 (Et2O/PE, 2:1). [α]2D3 = –10 (c
166.4 (ester CO) ppm. IR (film): ν = 3369, 3120, 2956, 2930, 2858,
˜
1720 (C=O), 1700 (C=O), 1655 (C=C), 1596 (C=C), 1499 (C=C),
1385, 1367, 1257, 1172, 838, 786 cm–1. UV/Vis (CH3CN): λmax (ε)
1
= 1.46, CHCl3). H NMR (400 MHz, C2D2Cl4, 90 °C): δ = 0.1 (s,
=
211 (17233 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for
3 H, SiCH3), 0.1 (s, 3 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3 (t,
C24H41NO6Si [M + H]+ 468.27759; found 468.27783.
3JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.4 [s, 9 H, OC(CH3)3], 2.1–2.4
3
(m, 3 H, 4-CH2, 5-CH), 2.4 (s, 3 H, CH3), 3.5 (dd, JH,H = 4.0, General Procedure for the Aza-Michael Additions Furnishing 2,5-
2JH,H = 10.5 Hz, 1 H, CH2OTBS), 3.5 (dd, JH,H = 6.0, JH,H
=
trans-Pyrrolidines: NaOEt (1.5 equiv.) was added under nitrogen at
3
2
10.5 Hz, 1 H, CH2OTBS), 4.2 (q, 3JH,H = 7.0 Hz, 2 H, OCH2CH3), –78 °C to a solution of the silylated Mannich product 5 in dry
3
3
4.7 (dd, JH,H = 5.5, JH,H = 8.5 Hz, 6-CH), 5.6 (br., 1 H, NH), DMF/THF (2:1, v/v; 0.1 ). After 40 min, a saturated NH4Cl solu-
3
3
3
5.9 (d, JH,H = 15.5 Hz, 1 H, 2-CH), 6.9 (dt, JH,H = 7.0, JH,H
=
tion was added. The aqueous phase was extracted three times with
ethyl acetate. The combined organic layers were washed twice with
3
15.5 Hz, 1 H, 3-CH), 7.1 (m, 3 H, ArH), 7.3 (t, JH,H = 7.5 Hz, 1
H, ArH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = –5.6 water and once with brine, dried with MgSO4, and filtered, and the
(SiCH3), 14.4 (OCH2CH3), 18.2 [SiC(CH3)3], 21.6 (CH3), 26.0 solvents were evaporated in vacuo. The residue was dissolved in a
[SiC(CH3)3], 28.5 [OC(CH3)3], 31.2 (C4), 44.8 (C5), 57.3 (C6), 60.3
(OCH2CH3), 63.0 (CH2OTBS), 79.1 [OC(CH3)3], 123.3 (C2), 124.3
(C6Ј), 128.1, 128.2, 128.3 (C2Ј, C4Ј, C5Ј), 137.9 (C3Ј), 140.2 (C1Ј),
147.0 (C3), 155.3 (carbamate CO), 166.4 (ester CO) ppm. IR (film):
small amount of diethyl ether, adsorbed on silica gel and purified
by flash column chromatography on silica gel (1:100, w/w) with
diethyl ether/petroleum ether (1:5, v/v) as eluent.
tert-Butyl (2S,3S,5S)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-(2-
ethoxy-2-oxoethyl)-2-phenylpyrrolidine-1-carboxylate (6a): Yield:
75 mg, 90%, oil. Rf = 0.38 (Et2O/PE, 1:2). [α]2D2 = –41 (c = 1.23,
CHCl3). 1H NMR (300 MHz, C2D2Cl4, 90 °C): δ = 0.1 (s, 6 H,
SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.2 [br., 9 H, OC(CH3)3], 1.3 (t,
ν = 3368, 3270, 3131, 2956, 2929, 2858, 1720 (C=O), 1700 (C=O),
˜
1653 (C=C), 1608 (C=C), 1591 (C=C), 1495 (C=C), 1385, 1366,
1257, 1172, 838, 787 cm–1. UV/Vis (CH3CN): λmax (ε) = 205
(30539), 213 (31290 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for
C27H45NO5Si [M + H]+ 492.31398; found 492.31437.
3
2
3JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.7 (dt, JH,H = 4.5, JH,H
=
Ethyl (2E,5S,6S)-6-[(tert-Butoxycarbonyl)amino]-5-{[(tert-butyldi-
15.0 Hz, 1 H, 4-CH2), 2.2 (mc, 1 H, 3-CH), 2.4–2.5 (m, 2 H, 4-
2
methylsilyl)oxy]methyl}-6-(2-methylphenyl)hex-2-enoate (5g): Yield: CH2, CH2CO2Et), 3.4 (br. d, JH,H = 15.5 Hz, 1 H, CH2CO2Et),
3
2
356 mg, 93%, viscous oil. Rf = 0.55 (Et2O/PE, 2:1). [α]2D3 = –29 (c
3.6 (dd, JH,H = 6.0, JH,H = 10.0 Hz, 1 H, CH2OTBS), 3.7 (dd,
1
2
3
= 1.10, CHCl3). H NMR (300 MHz, C2D2Cl4, 90 °C): δ = 0.0 (s,
3JH,H = 7.0, JH,H = 10.0 Hz, 1 H, CH2OTBS), 4.2 (q, JH,H
=
=
3
3 H, SiCH3), 0.1 (s, 3 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3 (t, 7.0 Hz, 2 H, OCH2CH3), 4.5 (mc, 1 H, 5-CH), 4.7 (d, JH,H
3JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.4 [s, 9 H, OC(CH3)3], 2.1 (br.,
4.0 Hz, 1 H, 2-CH), 7.2 (br. d, JH,H = 7.5 Hz, 2 H, 2Ј-CH, 6Ј-
3
3
3
1 H, 5-CH), 2.3–2.5 (m, 2 H, 4-CH2), 2.4 (s, 3 H, CH3), 3.5 (dd, CH), 7.2 (br. t, JH,H = 7.5 Hz, 1 H, 4Ј-CH), 7.3 (br. t, JH,H
=
7.5 Hz, 2 H, 3Ј-CH, 5Ј-CH) ppm. 13C NMR (50 MHz, CDCl3,
25 °C): δ = –5.2 (SiCH3), 14.4 (OCH2CH3), 18.4 [SiC(CH3)3], 26.0
[SiC(CH3)3], 28.1 [OC(CH3)3], 31.6 (C4), 39.7 (CH2CO2Et), 50.1
(C3), 55.3 (C5), 60.4 (OCH2CH3), 64.5 (CH2OTBS), 65.2 (C2), 79.5
2
3
3JH,H = 4.5, JH,H = 10.5 Hz, 1 H, CH2OTBS), 3.6 (dd, JH,H
=
5.5, 2JH,H = 10.5 Hz, 1 H, CH2OTBS), 4.2 (q, 3JH,H = 7.0 Hz, 2 H,
OCH2CH3), 5.0–5.1 (m, 2 H, 6-CH, NH), 5.9 (d, JH,H = 15.5 Hz,
1 H, 2-CH), 6.9 (dt, JH,H = 7.5, JH,H = 15.5 Hz, 1 H, 3-CH), 7.2
3
3
3
(m, 4 H, ArH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = –5.6 [OC(CH3)3], 125.6 (C4Ј), 126.7 (C2Ј, C6Ј), 128.4 (C3Ј, C5Ј), 145.3
(SiCH3), 14.5 (OCH2CH3), 18.3 [SiC(CH3)3], 19.7 (CH3), 26.0 (C1Ј), 154.4 (carbamate CO), 171.9 (ester CO) ppm. IR (film): ν =
˜
[SiC(CH3)3], 28.5 [OC(CH3)3], 30.1 (C4), 44.9 (C5), 52.4 (C6), 60.3
(OCH2CH3), 62.7 (CH2OTBS), 79.3 [OC(CH3)3], 122.9 (C2), 126.0, 1385, 1306, 1255, 1162, 1127, 838, 786, 700 cm–1. UV/Vis
126.1 (C4Ј, C5Ј), 127.1 (C6Ј), 130.9 (C3Ј), 136.0 (C2Ј), 139.6 (C1Ј), (CH3CN): λmax (ε) 207 (13151), 260 (1002), 280
3064, 3030, 2955, 2930, 2858, 1735, 1694, 1604, 1495, 1472, 1455,
=
147.6 (C3), 155.4 (carbamate CO), 166.5 (ester CO) ppm. IR (film): (710 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for C26H43NO5Si [M
ν = 3367, 3275, 3132, 2956, 2930, 2858, 1720 (C=O), 1698 (C=O), + H]+ 478.29833; found 478.29821.
˜
1653 (C=C), 1605 (C=C), 1495 (C=C), 1385, 1366, 1258, 1170, 838,
tert-Butyl (2S,3S,5S)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-(2-
ethoxy-2-oxoethyl)-2-(4-fluorophenyl)pyrrolidine-1-carboxylate (6b):
Yield: 65 mg, 84%, oil. Rf = 0.33 (Et2O/PE, 1:2). [α]2D2 = –40 (c =
787 cm–1. UV/Vis (CH3CN): λmax (ε)
= 205 (23441), 210
(23358 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for C27H45NO5Si
[M + H]+ 492.31398; found 492.31366.
1
1.01, CHCl3). H NMR (300 MHz, C2D2Cl4, 90 °C): δ = 0.1 (s, 3
Ethyl (2E,5S,6S)-6-[(tert-Butoxycarbonyl)amino]-5-{[(tert-butyldi-
H, SiCH3), 0.1 (s, 3 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.2 [s, 9 H,
3
3
methylsilyl)oxy]methyl}-6-(2-furyl)hex-2-enoate (5h): Yield: 344 mg, OC(CH3)3], 1.3 (t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.7 (dt, JH,H
2
70%, viscous oil. Rf = 0.67 (Et2O/PE, 2:1). [α]2D4 = –21 (c = 1.15,
= 4.5, JH,H = 13.5 Hz, 1 H, 4-CH2), 2.2–2.3 (m, 1 H, 3-CH), 2.4–
CHCl3). 1H NMR (400 MHz, C2D2Cl4, 90 °C): δ = 0.1 (s, 6 H,
2.5 (m, 2 H, 4-CH2, CH2CO2Et), 3.4 (dd, JH,H = 3.0, JH,H =
3
2
3
3
2
SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3 (t, JH,H = 7.0 Hz, 3 H, 15.5 Hz, 1 H, CH2CO2Et), 3.6 (dd, JH,H = 6.0, JH,H = 10.0 Hz,
3
2
OCH2CH3), 1.5 [s, 9 H, OC(CH3)3], 2.2–2.4 (m, 3 H, 4-CH2, 5- 1 H, CH2OTBS), 3.7 (dd, JH,H = 7.0, JH,H = 10.0 Hz, 1 H,
3
2
3
CH), 3.5 (dd, JH,H = 4.0, JH,H = 10.0 Hz, 1 H, CH2OTBS), 3.6
CH2OTBS), 4.2 (q, JH,H = 7.0 Hz, 2 H, OCH2CH3), 4.4 (mc, 1 H,
(dd, JH,H = 6.0, JH,H = 10.0 Hz, 1 H, CH2OTBS), 4.2 (q, JH,H 5-CH), 4.7 (d, 3JH,H = 4.0 Hz, 1 H, 2-CH), 7.0 (br. t, JH,H = 3JH,F
3
2
3
3
3
3
= 7.0 Hz, 2 H, OCH2CH3), 4.9 (dd, JH,H = 5.0, JH,H = 9.0 Hz, 1
= 8.5 Hz, 2 H, 3Ј-CH, 5Ј-CH), 7.1 (m, 2Ј-CH, 6Ј-CH) ppm. 13C
–5.2 (SiCH3), 14.4
1 H, 2-CH), 6.2 (d, JH,H = 3.0 Hz, 1 H, 3-furyl-H), 6.4 (dd, JH,H (OCH2CH3), 18.4 [SiC(CH3)3], 26.0 [SiC(CH3)3], 28.1 [OC(CH3)3],
H, 6-CH), 5.5 (br., 1 H, NH), 5.9 (dt, 4JH,H = 1.5, 3JH,H = 15.5 Hz, NMR (100 MHz, CDCl3, 25 °C):
δ
=
3
3
3
3
3
= 2.0, JH,H = 3.0 Hz, 1 H, 4-furyl-H), 7.0 (dt, JH,H = 7.0, JH,H
31.6 (C4), 39.6 (CH2CO2Et), 50.2 (C3), 55.2 (C5), 60.4
(OCH2CH3), 64.4 (CH2OTBS), 64.5 (C2), 79.7 [OC(CH3)3], 115.2
(2JC,F = 21.0 Hz, C3Ј, C5Ј), 127.1 (3JC,F = 8.0 Hz, C2Ј, C6Ј), 141.1
4
3
= 15.5 Hz, 1 H, 3-CH), 7.4 (dd, JH,H = 0.5, JH,H = 2.0 Hz, 1 H,
5-furyl-H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = –5.6
5558
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5549–5564

Stereodivergent Synthesis of Highly Substituted Pyrrolidines
(C1Ј), 154.2 (carbamate CO), 161.7 (1JC,F = 242.5 Hz, C4Ј), 171.8
CH2OTBS), 3.7 (dd, 3JH,H = 7.0, 2JH,H = 10.0 Hz, 1 H, CH2OTBS),
3
(ester CO) ppm. IR (film): ν = 3050, 3025, 2955, 2930, 2896, 2859, 4.2 (q, JH,H = 7.0 Hz, 2 H, OCH2CH3), 4.4 (mc, 1 H, 5-CH), 4.7
˜
3
1735 (C=O), 1695 (C=O), 1606 (C=C), 1510 (C=C), 1472, 1385,
(br., 1 H, 2-CH), 7.0 (br. d, JH,H = 8.0 Hz, 2 H, ArH), 7.1 (br. d,
1255, 1226, 1156, 837, 785 cm–1. UV/Vis (CH3CN): λmax (ε) = 201 3JH,H = 8.0 Hz, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3,
(9041), 265 (1103), 271 (1018 mol–1 dm3 cm–1) nm. HRMS-ESI:
calcd. for C26H42FNO5Si [M + H]+ 496.28895; found 496.28895.
25 °C): δ = –5.3 (SiCH3), 14.4 (OCH2CH3), 18.4 [SiC(CH3)3], 21.1
(CH3), 26.0 [SiC(CH3)3], 28.1 [OC(CH3)3], 31.5 (C4), 39.7
(CH2CO2Et), 50.1 (C3), 55.1 (C5), 60.4 (OCH2CH3), 64.5
(CH2OTBS), 64.9 (C2), 79.4 [OC(CH3)3], 125.5 (C2Ј, C6Ј), 129.0
(C3Ј, C5Ј), 136.1 (C4Ј), 142.2 (C1Ј), 154.5 (carbamate CO), 171.9
tert-Butyl (2S,3S,5S)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-2-(4-
chlorophenyl)-5-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate (6c):
Yield: 59 mg, 88%, oil. Rf = 0.33 (Et2O/PE, 1:2). [α]2D4 = –35 (c =
(ester CO) ppm. IR (film): ν = 2955, 2930, 2858, 1736 (C=O), 1695
˜
1
1.13, CHCl3). H NMR (400 MHz, C2D2Cl4, 90 °C): δ = 0.1 (s, 3
(C=O), 1514 (C=C), 1388, 1366, 1254, 1161, 1112, 838, 778 cm–1.
UV/Vis (CH3CN): λmax (ε) = 216 (10264), 266 (456), 273
(376 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for C27H45NO5Si [M
+ H]+ 492.31398; found 492.31408.
H, SiCH3), 0.1 (s, 3 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3 [br., 9
3
H, OC(CH3)3], 1.3 (t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.7 (dt,
2
3JH,H = 4.5, JH,H = 13.5 Hz, 1 H, 4-CH2), 2.2 (m, 1 H, 3-CH),
2
2.4–2.5 (m, 2 H, 4-CH2, CH2CO2Et), 3.4 (br. d, JH,H = 15.0 Hz,
tert-Butyl (2S,3S,5S)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-(2-
ethoxy-2-oxoethyl)-2-(3-methylphenyl)pyrrolidine-1-carboxylate (6f):
Yield: 48 mg, 94%, oil. Rf = 0.33 (Et2O/PE, 1:2). [α]2D4 = –45 (c =
3
2
1 H, CH2CO2Et), 3.6 (dd, JH,H = 6.0, JH,H = 10.0 Hz, 1 H,
CH2OTBS), 3.7 (dd, 3JH,H = 7.5, 2JH,H = 10.0 Hz, 1 H, CH2OTBS),
3
4.2 (q, JH,H = 7.0 Hz, 2 H, OCH2CH3), 4.4 (mc, 1 H, 5-CH), 4.7
1
1.16, CHCl3). H NMR (400 MHz, C2D2Cl4, 90 °C): δ = 0.1 (s, 6
(br. d, 3JH,H = 3.5 Hz, 1 H, 2-CH), 7.1 (br. d, JH,H = 8.5 Hz, 2 H,
3
H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.2 [br., 9 H, OC(CH3)3], 1.3
ArH), 7.3 (br. d, JH,H = 8.5 Hz, 2 H, ArH) ppm. 13C NMR
3
3
3
2
(t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.7 (dt, JH,H = 4.5, JH,H
=
(100 MHz, CDCl3, 25 °C): δ = –5.3 (SiCH3), 14.4 (OCH2CH3), 18.4
[SiC(CH3)3], 26.0 [SiC(CH3)3], 28.1 [OC(CH3)3], 31.5 (C4), 39.6
(CH2CO2Et), 50.1 (C3), 55.2 (C5), 60.4 (OCH2CH3), 64.4
(CH2OTBS), 64.6 (C2), 79.8 [OC(CH3)3], 127.0 (C3Ј, C5Ј), 128.5
(C2Ј, C6Ј), 132.3 (C4Ј), 143.9 (C1Ј), 154.2 (carbamate CO), 171.8
13.5 Hz, 1 H, 4-CH2), 2.2 (mc, 1 H, 3-CH), 2.4 (s, 3 H, CH3), 2.4–
2
2.5 (m, 2 H, 4-CH2, CH2CO2Et), 3.4 (br. d, JH,H = 15.5 Hz, 1 H,
3
2
CH2CO2Et), 3.6 (dd, JH,H = 6.0, JH, H = 10.0 Hz, 1 H,
CH2OTBS), 3.7 (dd, 3JH,H = 7.0, 2JH,H = 10.0 Hz, 1 H, CH2OTBS),
3
4.2 (q, JH,H = 7.0 Hz, 2 H, OCH2CH3), 4.5 (mc, 1 H, 5-CH), 4.7
(ester CO) ppm. IR (film): ν = 2955, 2930, 2858, 1735 (C=O), 1600
˜
3
(br., 1 H, 2-CH), 7.0 (d, JH,H = 7.5 Hz, 1 H, 4Ј-CH), 7.0 (s, 1 H,
(C=C), 1580 (C=C), 1697 (C=O), 1492 (C=C), 1388, 1366, 1255,
1163, 1093, 838, 777 cm–1. UV/Vis (CH3CN): λmax (ε) = 201
(17044), 222 (14340), 267 (1106 mol–1 dm3 cm–1) nm. HRMS-ESI:
calcd. for C26H42ClNO5Si [M + H]+ 512.29530; found 512.25892.
2Ј-CH), 7.1 (d, 3JH,H = 7.5 Hz, 1 H, 6Ј-CH), 7.2 (t, 3JH,H = 7.5 Hz,
1 H, 5Ј-CH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = –5.2
(SiCH3), 14.4 (OCH2CH3), 18.4 [SiC(CH3)3], 21.6 (CH3), 26.0
[SiC(CH3)3], 28.1 [OC(CH3)3], 31.7 (C4), 39.7 (CH2CO2Et), 50.1
(C3), 55.3 (C5), 60.4 (OCH2CH3), 64.5 (CH2OTBS), 65.1 (C2), 79.5
[OC(CH3)3], 122.8, 126.3, 127.3, 128.3 (Car), 137.9 (C3Ј), 145.2
tert-Butyl (2S,3S,5S)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-(2-
ethoxy-2-oxoethyl)-2-(4-methoxyphenyl)pyrrolidine-1-carboxylate
(6d): Yield: 62 mg, 85%, oil. Rf = 0.33 (Et2O/PE, 1:2). [α]2D4 = –37
(C1Ј), 154.5 (carbamate CO), 171.9 (ester CO) ppm. IR (film): ν =
˜
1
(c = 1.19, CHCl3). H NMR (400 MHz, C2D2Cl4, 90 °C): δ = 0.1
2955, 2930, 2858, 1736 (C=O), 1695 (C=O), 1609 (C=C), 1389,
1366, 1255, 1175, 1126, 838, 777 cm–1. UV/Vis (CH3CN): λmax (ε)
= 265 (852 mol– 1 dm3 cm– 1 ) nm. HRMS-ESI: calcd. for
C27H45NO5Si [M + H]+ 492.31398; found 492.31382.
(s, 6 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.2 [br. s, 9 H, OC-
3
3
(CH3)3], 1.3 (t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.7 (dt, JH,H
=
2
4.5, JH,H = 13.5 Hz, 1 H, 4-CH2), 2.2 (mc, 1 H, 3-CH), 2.4 (m, 2
H, 4-CH2, CH2CO2Et), 3.4 (br. d, JH,H = 15.5 Hz, 1 H,
2
tert-Butyl (2S,3S,5S)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-(2-
ethoxy-2-oxoethyl)-2-(2-methylphenyl)pyrrolidine-1-carboxylate
(6g): Yield: 59 mg, 81%, oil. Rf = 0.33 (Et2O/PE, 1:2). [α]2D4 = –23
3
2
CH2CO2Et), 3.6 (dd, JH,H = 6.5, JH, H = 10.0 Hz, 1 H,
CH2OTBS), 3.7 (dd, 3JH,H = 7.5, 2JH,H = 10.0 Hz, 1 H, CH2OTBS),
3
3.8 (s, 3 H, OCH3), 4.2 (q, JH,H = 7.0 Hz, 2 H, OCH2CH3), 4.4
1
(c = 1.11, CHCl3). H NMR (400 MHz, C2D2Cl4, 90 °C): δ = 0.1
3
(mc, 1 H, 5-CH), 4.7 (d, JH,H = 2.5 Hz, 1 H, 2-CH), 6.9 (br. d,
(s, 6 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.2 [br. s, 9 H, OC-
3JH,H = 8.5 Hz, 2 H, ArH), 7.1 (br. d, JH,H = 8.5 Hz, 2 H, ArH)
3
3
3
(CH3)3], 1.3 (t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.8 (dt, JH,H
=
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = –5.3 (SiCH3), 14.4
(OCH2CH3), 18.4 [SiC(CH3)3], 26.0 [SiC(CH3)3], 28.1 [OC(CH3)3],
31.6 (C4), 39.7 (CH2CO2Et), 50.1 (C3), 55.1 (C5), 55.4 (OCH3),
60.4 (OCH2CH3), 64.5 (CH2OTBS), 64.6 (C2), 79.4 [OC(CH3)3],
113.7 (C3Ј, C5Ј), 126.7 (C2Ј, C6Ј), 137.5 (C1Ј), 154.4 (carbamate
3.5, 2JH,H = 13.5 Hz, 1 H, 4-CH2), 2.2 (m, 1 H, 3-CH), 2.4–2.5 (m,
2 H, 4-CH2, CH2CO2Et), 2.4 (s, 3 H, CH3), 3.4 (br. d, JH,H
2
=
3
2
15.5 Hz, CH2CO2Et), 3.7 (dd, JH,H = 6.0, JH,H = 10.0 Hz, 1 H,
CH2OTBS), 3.8 (dd, 3JH,H = 7.5, 2JH,H = 10.0 Hz, 1 H, CH2OTBS),
3
4.2 (q, JH,H = 7.0 Hz, 2 H, OCH2CH3), 4.5 (mc, 1 H, 5-CH), 5.0
CO), 158.4 (C4Ј), 171.9 (ester CO) ppm. IR (film): ν = 2955, 2930,
˜
3
3
(d, JH,H = 3.0 Hz, 1 H, 2-CH), 7.0 (br. d, JH,H = 7.0 Hz, 1 H,
ArH), 7.1–7.2 (m, 3 H, ArH) ppm. 13C NMR (100 MHz, CDCl3,
25°): δ = –5.3 (SiCH3), 14.4 (OCH2CH3), 18.5 [SiC(CH3)3], 19.6
(CH3), 26.1 [SiC(CH3)3], 28.0 [OC(CH3)3], 31.2 (C4), 39.9
(CH2CO2Et), 48.8 (C3), 55.3 (C5), 60.4 (OCH2CH3), 61.7 (C2),
65.0 (CH2OTBS), 79.4 [OC(CH3)3], 124.4 (C5Ј), 126.2 (C4Ј), 126.5
(C6Ј), 130.2 (C3Ј), 134.6 (C2Ј), 143.2 (C1Ј), 154.5 (carbamate CO),
2858, 1735 (C=O), 1694 (C=O), 1614 (C=C), 1590 (C=C), 1513
(C=C) 1389, 1366, 1250, 1174, 1111, 837, 787 cm–1. UV/Vis
(CH3CN): λmax (ε) = 226 (17250), 277 (2987 mol–1 dm3 cm–1) nm.
HRMS-ESI: calcd. for C27H45NO6Si [M + H]+ 508.30889; found
508.30840.
tert-Butyl (2S,3S,5S)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-(2-
ethoxy-2-oxoethyl)-2-(4-methylphenyl)pyrrolidine-1-carboxylate
(6e): Yield: 66 mg, 92%, oil. Rf = 0.33 (Et2O/PE, 1:2). [α]2D4 = –42
171.9 (ester CO) ppm. IR (film): ν = 2956, 2930, 2858, 1736 (C=O),
˜
1695 (C=O), 1605 (C=C), 1389, 1366, 1255, 1164, 1129, 1104, 838,
787 cm–1. UV/Vis (CH3CN): λmax (ε) = 202 (17167), 263
(418 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for C27H45NO5Si [M
+ H]+ 492.31398; found 492.31368. HRMS-ESI: calcd. for [M +
Na]+ 514.29592; found 514.29617.
1
(c = 1.24, CHCl3). H NMR (400 MHz, C2D2Cl4, 90 °C): δ = 0.1
(s, 6 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.2 [br., 9 H, OC(CH3)3],
3
3
2
1.3 (t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.7 (dt, JH,H = 4.5, JH,H
= 13.5 Hz, 1 H, 4-CH2), 2.2 (mc, 1 H, 3-CH), 2.4 (m, 2 H, 4-CH2,
2
CH2CO2Et), 2.4 (s, 3 H, CH3), 3.4 (br. d, JH,H = 15.0 Hz, 1 H,
tert-Butyl (2S,3S,5S)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-(2-
3
2
CH2CO2Et), 3.6 (dd, JH,H = 6.5, JH, H = 10.0 Hz, 1 H, ethoxy-2-oxoethyl)-2-(2-furyl)pyrrolidine-1-carboxylate (6h): Yield:
Eur. J. Org. Chem. 2009, 5549–5564
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5559

C. Enkisch, C. Schneider
FULL PAPER
65 mg, 92%, oil. Rf = 0.33 (Et2O/PE, 1:2). [α]2D4 = –44 (c = 1.26,
OC(CH3)3], 1.3 (t, 3JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.9 (ddd, 3JH,H
3
2
3
CHCl3). 1H NMR (300 MHz, C2D2Cl4, 90 °C): δ = 0.1 (s, 6 H,
= 4.0, JH,H = 7.0, JH,H = 13.0 Hz, 1 H, 4-CH2), 2.1 (dt, JH,H
=
3
SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3 (t, JH,H = 7.0 Hz, 3 H,
8.0, 2JH,H = 13.0 Hz, 1 H, 4-CH2), 2.3–2.4 (m, 1 H, 3-CH), 2.5 (dd,
3
2
2
3
OCH2CH3), 1.3 [s, 9 H, OC(CH3)3], 1.7 (dt, JH,H = 4.0, JH,H
=
3JH,H = 10.0, JH,H = 15.0 Hz, 1 H, CH2CO2Et), 3.2 (dd, JH,H
=
3
2
2
3
2
13.0 Hz, 1 H, 4-CH2), 2.4 (dd, JH,H = 10.0, JH,H = 15.0 Hz, 1 H,
4.0, JH,H = 15.0 Hz, 1 H, CH2CO2Et), 3.6 (dd, JH,H = 5.5, JH,H
CH2CO2Et), 2.4–2.5 (m, 2 H, 3-CH, 4-CH2), 3.4 (dd, JH,H = 3.5, = 10.0 Hz, 1 H, CH2OTBS), 3.7 (dd, 3JH,H = 5.5, 2JH,H = 10.0 Hz,
3
3
2
3
2JH,H = 15.5 Hz, 1 H, CH2CO2Et), 3.6 (dd, JH,H = 6.0, JH,H
=
1 H, CH2OTBS), 4.2 (q, JH,H = 7.0 Hz, 2 H, OCH2CH3), 4.4 (mc,
3
2
3
3
10.0 Hz, 1 H, CH2OTBS), 3.7 (dd, JH,H = 7.0, JH,H = 10.0 Hz, 1 1 H, 5-CH), 4.7 (d, JH,H = 6.5 Hz, 1 H, 2-CH), 7.1 (br. t, JH,H
=
H, CH2OTBS), 4.2 (q, JH,H = 7.0 Hz, OCH2CH3), 4.8 (m, 1 H, 5- 3JH,F = 8.5 Hz, 2 H, 3Ј-CH, 5Ј-CH), 7.2 (m, 2Ј-CH, 6Ј-CH) ppm.
3
3
3
CH), 4.8 (d, JH,H = 3.0 Hz, 1 H, 2-CH), 6.1 (d, JH,H = 3.0 Hz, 1
H, 3Ј-CH), 6.3 (dd, JH,H = 2.0, JH,H = 3.0 Hz, 1 H, 4Ј-CH), 7.3 (OCH2CH3), 18.4 [SiC(CH3)3], 26.0 [SiC(CH3)3], 28.3 [OC(CH3)3],
13C NMR (100 MHz, CDCl3, 25 °C): δ = –5.3 (SiCH3), 14.3
3
3
(dd, JH,H = 2.0, JH,H = 0.5 Hz, 1 H, 5Ј-CH) ppm. 13C NMR 32.6 (C4), 40.5 (CH2CO2 Et), 49.4 (C3), 55.2 (C5), 60.6
(75 MHz, CDCl3, 25 °C): δ = –5.3 (SiCH3), 14.4 (OCH2CH3), 18.4 (OCH2CH3), 62.6 (CH2OTBS), 63.8 (C2), 79.9 [OC(CH3)3], 115.1
[SiC(CH3)3], 26.0 [SiC(CH3)3], 28.2 [OC(CH3)3], 31.8 (C4), 39.8 (2JC,F = 20.5 Hz, C3Ј, C5Ј), 127.5 (3JC,F = 7.5 Hz, C2Ј, C6Ј), 139.8
(CH2CO2Et), 46.7 (C3), 54.3 (C5), 58.4 (C2), 60.4 (OCH2CH3), (C1Ј), 154.7 (carbamate CO), 161.8 (1JC,F = 244.0 Hz, C4Ј), 171.4
3
4
64.1 (CH2OTBS), 79.7 [OC(CH3)3], 105.4 (C3Ј), 110.2 (C4Ј), 141.1
(C5Ј), 154.5 (carbamate CO), 156.2 (C2Ј), 171.8 (ester CO) ppm.
(ester CO) ppm. IR (film): ν = 3040, 3020, 2955, 2930, 2858, 1736
˜
(C=O), 1697 (C=O), 1606 (C=C), 1510 (C=C), 1384, 1253, 1225,
IR (film): ν = 2956, 2930, 2858, 1736 (C=O), 1699 (C=O), 1366, 1155, 1134, 837, 787 cm–1. UV/Vis (CH3CN): λmax (ε) = 265 (1460),
˜
1255, 1162, 1121, 838, 786, 763 cm–1. UV/Vis (CH3CN): λmax (ε) = 271 (1283 mol– 1 dm3 cm– 1 ) nm. HRMS-ESI: calcd. for
217 (19373), 297 (2461), 310 (2590), 355 (1906 mol–1 dm3 cm–1) nm. C26H42FNO5Si [M + H]+ 496.28895; found 496.28895.
HRMS-ESI: calcd. for C24H41NO6Si [M + H]+ 468.27759; found
tert-Butyl (2S,3S,5R)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-2-(4-
468.27723.
chlorophenyl)-5-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate (7c):
Yield: 63 mg, 86%, oil. Rf = 0.38 (Et2O/PE, 1:2). [α]2D4 = +17 (c =
General Procedure for the Aza-Michael Additions Furnishing 2,5-
1
1.05, CHCl3). H NMR (400 MHz, C2D2Cl4, 90 °C): δ = 0.1 (s, 3
H, SiCH3), 0.1 (s, 3 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3 (t, 3JH,H
= 7.0 Hz, 3 H, OCH2CH3), 1.3 [br., 9 H, OC(CH3)3], 1.9 (ddd,
cis-Pyrrolidines: KOtBu (1.0 equiv.) was added under nitrogen at
–78 °C to a solution of the silylated Mannich product 5 in dry
DMF/THF (2:1, v/v; 0.1 ). After 40 min, a saturated NH4Cl solu-
tion was added. The aqueous phase was extracted three times with
ethyl acetate. The combined organic layers were washed twice with
water and once with brine, dried with MgSO4, and filtered, and the
solvents were evaporated in vacuo. The residue was dissolved in a
small amount of diethyl ether, adsorbed on silica gel, and purified
by flash column chromatography on silica gel (1:100, w/w) with
diethyl ether/petroleum ether (1:5, v/v) as eluent.
3JH,H = 4.0, JH,H = 7.0, JH,H = 13.0 Hz, 1 H, 4-CH2), 2.1 (dt,
3JH,H = 8.0, 2JH,H = 13.0 Hz, 1 H, 4-CH2), 2.3 (m, 1 H, 3-CH), 2.5
(dd, 3JH,H = 10.0, 2JH,H = 15.0 Hz, 1 H, CH2CO2Et), 3.2 (dd, 3JH,H
3
2
2
3
= 4.0, JH,H = 15.0 Hz, 1 H, CH2CO2Et), 3.7 (d, JH,H = 6.0 Hz,
3
2 H, CH2OTBS), 4.2 (q, JH,H = 7.0 Hz, 2 H, OCH2CH3), 4.4 (m,
1 H, 5-CH), 4.7 (d, JH,H = 6.5 Hz, 1 H, 2-CH), 7.2 (br. d, JH,H
= 8.5 Hz, 2 H, ArH), 7.3 (br. d, JH,H = 8.5 Hz, 2 H, ArH) ppm.
3
3
3
13C NMR (75 MHz, CDCl3, 25 °C): δ = –5.3 (SiCH3), 14.3
(OCH2CH3), 18.4 [SiC(CH3)3], 26.0 [SiC(CH3)3], 28.3 [OC(CH3)3],
32.6 (C4), 40.5 (CH2CO2 Et), 49.4 (C3), 55.2 (C5), 60.6
(OCH2CH3), 62.6 (CH2OTBS), 63.8 (C2), 80.0 [OC(CH3)3], 127.4
(C3Ј, C5Ј), 128.5 (C2Ј, C6Ј), 132.4 (C4Ј), 142.7 (C1Ј), 154.7 (carba-
tert-Butyl (2S,3S,5R)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-(2-
ethoxy-2-oxoethyl)-2-phenylpyrrolidine-1-carboxylate (7a): Yield:
64 mg, 88%, oil. Rf = 0.47 (Et2O/PE, 1:2). [α]2D4 = +20 (c = 1.21,
CHCl3). 1H NMR (300 MHz, C2D2Cl4, 90 °C): δ = 0.1 (s, 3 H,
SiCH3), 0.1 (s, 3 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3 [s, 9 H,
OC(CH3)3], 1.3 (t, 3JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.9 (ddd, 3JH,H
mate CO), 171.4 (ester CO) ppm. IR (film): ν = 2956, 2930, 2858,
˜
1736 (C=O), 1698 (C=O), 1492 (C=C), 1383, 1367, 1253, 1159,
1092, 837, 786, 763 cm–1. UV/Vis (CH3CN): λmax (ε) = 222 (9152),
2 6 7 ( 4 04 m o l – 1 d m 3 c m – 1 ) nm. HRMS-ESI: calcd. for
C26H42ClNO5Si [M + H]+ 512.29530; found 512.25892.
3
2
3
= 4.0, JH,H = 7.0, JH,H = 13.0 Hz, 1 H, 4-CH2), 2.1 (dt, JH,H
=
8.0, 2JH,H = 13.0 Hz, 1 H, 4-CH2), 2.3–2.4 (m, 1 H, 3-CH), 2.5 (dd,
3JH,H = 10.0, JH,H = 15.0 Hz, 1 H, CH2CO2Et), 3.2 (dd, JH,H
=
=
2
3
2
3
2
4.0, JH,H = 15.0 Hz, CH2CO2Et), 3.6 (dd, JH,H = 5.5, JH,H
10.0 Hz, 1 H, CH2OTBS), 3.7 (dd, JH,H = 5.5, JH,H = 10.0 Hz, 1
H, CH2OTBS), 4.2 (q, JH,H = 7.0 Hz, 2 H, OCH2CH3), 4.4 (mc,
1 H, 5-CH), 4.7 (d, JH,H = 6.5 Hz, 1 H, 2-CH), 7.2–7.3 (m, 3 H,
tert-Butyl (2S,3S,5R)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-(2-
ethoxy-2-oxoethyl)-2-(4-methoxyphenyl)pyrrolidine-1-carboxylate
(7d): Yield: 66 mg, 83%, oil. Rf = 0.38 (Et2O/PE, 1:2). [α]2D4 = +24
3
2
3
3
1
(c = 1.23, CHCl3). H NMR (400 MHz, C2D2Cl4, 90 °C): δ = 0.1
ArH), 7.3–7.4 (m, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = –5.3 (SiCH3), 14.3 (OCH2CH3), 18.4 [SiC(CH3)3], 26.0
[SiC(CH3)3], 28.2 [OC(CH3)3], 32.7 (C4), 40.4 (CH2CO2Et), 49.3
(C3), 55.1 (C5), 60.5 (OCH2CH3), 62.6 (CH2OTBS), 64.3 (C2), 79.7
[OC(CH3)3], 126.0 (C4Ј), 126.7 (C2Ј, C6Ј), 128.3 (C3Ј, C5Ј), 144.0
(s, 3 H, SiCH3), 0.1 (s, 3 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3 (t,
3JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.3 [br. s, 9 H, OC(CH3)3], 1.9
3
3
2
(ddd, JH,H = 4.5, JH,H = 6.5, JH,H = 13.0 Hz, 1 H, 4-CH2), 2.1
(dt, JH,H = 8.0, 2JH,H = 13.0 Hz, 1 H, 4-CH2), 2.3–2.4 (m, 1 H, 3-
3
CH), 2.5 (dd, 3JH,H = 10.0, 2JH,H = 15.0 Hz, 1 H, CH2CO2Et), 3.21
(C1Ј), 154.7 (carbamate CO), 171.5 (ester CO) ppm. IR (film): ν =
˜
3
2
(dd, JH,H = 4.0, JH,H = 15.0 Hz, 1 H, CH2CO2Et), 3.6 (mc, 2 H,
3065, 3030, 2955, 2929, 2857, 1736, 1694, 1604, 1495, 1455, 1385,
1253, 1157, 1135, 837, 787, 699 cm–1. UV/Vis (CH3CN): λmax (ε) =
202 (9157), 207 (8295), 232 (4418), 269 (2966 mol–1 dm3 cm–1) nm.
HRMS-ESI: calcd. for C26H43NO5Si [M + H]+ 478.29833; found
478.29821.
CH2OTBS), 4.2 (q, 3J = 7.0 Hz, 2 H, OCH2CH3), 4.3–4.4 (m, 1 H,
3
3
5-CH), 4.6 (d, JH,H = 6.0 Hz, 1 H, 2-CH), 6.9 (br. d, JH,H
=
8.5 Hz, 2 H, ArH), 7.2 (br. d, 3JH,H = 8.5 Hz, 2 H, ArH) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = –5.3 (SiCH3 ), 14.3
(OCH2CH3), 18.4 [SiC(CH3)3], 26.0 [SiC(CH3)3], 28.3 [OC(CH3)3],
tert-Butyl (2S,3S,5R)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-(2- 32.6 (C4), 40.5 (CH2CO2Et), 49.3 (C3), 55.1 (C5), 55.4 (OCH3),
ethoxy-2-oxoethyl)-2-(4-fluorophenyl)pyrrolidine-1-carboxylate (7b):
60.5 (OCH2CH3), 62.7 (CH2OTBS), 63.7 (C2), 79.6 [OC(CH3)3],
113.7 (C3Ј, C5Ј), 127.1 (C2Ј, C6Ј), 136.1 (C1Ј), 154.8 (carbamate
Yield: 67 mg, 93%, oil. Rf = 0.38 (Et2O/PE, 1:2). [α]2D2 = +19 (c =
1
0.93, CHCl3). H NMR (300 MHz, C2D2Cl4, 90 °C): δ = 0.10 (s, 3 CO), 158.5 (C4Ј), 171.5 (ester CO) ppm. IR (film): ν = 2955, 2931,
˜
H, SiCH3), 0.1 (s, 3 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3 [s, 9 H,
5560
2857, 1736 (C=O), 1694 (C=O), 1614 (C=C), 1586 (C=C), 1513
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5549–5564

Stereodivergent Synthesis of Highly Substituted Pyrrolidines
(C=C), 1388, 1366, 1249, 1175, 1112, 1036, 836, 777 cm–1. UV/Vis ArH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = –5.4 (SiCH3),
(CH3CN): λmax (ε) = 226 (11735), 276 (2010 mol–1 dm3 cm–1) nm. 14.4 (OCH2CH3), 18.5 [SiC(CH3)3], 19.6 (CH3), 26.0 [SiC(CH3)3],
HRMS-ESI: calcd. for C27H45NO6Si [M + H]+ 508.30889; found
508.30840.
28.1 [OC(CH3)3], 32.4 (C4), 40.1 (CH2CO2Et), 49.1 (C3), 55.1 (C5),
60.4 (C2), 60.5 (OCH2CH3), 62.3 (CH2OTBS), 79.6 [OC(CH3)3],
125.0 (C5Ј), 126.1 (C4Ј), 126.5 (C6Ј), 130.1 (C3Ј), 135.3 (C2Ј), 142.3
tert-Butyl (2S,3S,5R)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-(2-
ethoxy-2-oxoethyl)-2-(4-methylphenyl)pyrrolidine-1-carboxylate
(7e): Yield: 67 mg, 88%, oil. Rf = 0.38 (Et2O/PE, 1:2). [α]2D4 = +20
(C1Ј), 154.8 (carbamate CO), 171.6 (ester CO) ppm. IR (film): ν =
˜
2956, 2930, 2858, 1736 (C=O), 1695 (C=O), 1390, 1366, 1254, 1158,
1133, 837, 786 cm–1. UV/Vis (CH3CN): λmax (ε)
= 264
1
(c = 1.02, CHCl3). H NMR (400 MHz, C2D2Cl4, 90 °C): δ = 0.1
(491 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for C27H45NO5Si [M
+ H]+ 492.31398; found 492.31368. HRMS-ESI: calcd. for [M +
Na]+ 514.29592; found 514.29617.
(s, 3 H, SiCH3), 0.1 (s, 3 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3 (t,
3JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.3 [br., 9 H, OC(CH3)3], 1.9
3
3
2
(ddd, JH,H = 4.5, JH,H = 7.0, JH,H = 13.0 Hz, 1 H, 4-CH2), 2.1
(dt, JH,H = 8.0, 2JH,H = 13.0 Hz, 1 H, 4-CH2), 2.1–2.8 (m, 1 H, 3-
CH), 2.4 (s, 3 H, CH3), 2.5 (dd, JH,H = 10.0, JH,H = 15.0 Hz, 1
tert-Butyl (2S,3S,5R)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-(2-
ethoxy-2-oxoethyl)-2-(2-furyl)pyrrolidine-1-carboxylate (7h): Yield:
66 mg, 88%, oil. Rf = 0.38 (Et2O/PE, 1:2). [α]2D2 = +7 (c = 1.20,
3
3
2
3
2
H, CH2CO2Et), 3.2 (dd, JH,H = 4.0, JH,H = 15.0 Hz, 1 H,
CH2CO2Et), 3.6 (mc, 2 H, CH2OTBS), 4.2 (q, JH,H = 7.0 Hz, 2 CHCl3). 1H NMR (300 MHz, C2D2Cl4, 90 °C): δ = 0.1 (s, 6 H,
3
3
3
H, OCH2CH3), 4.3–4.4 (m, 1 H, 5-CH), 4.7 (d, JH,H = 6.0 Hz, 1
SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3 (t, JH,H = 7.0 Hz, 3 H,
H, 2-CH), 7.0–7.1 (m, 4 H, ArH) ppm. 13C NMR (75 MHz, OCH2CH3), 1.4 [s, 9 H, OC(CH3)3], 2.0 (ddd, 3JH,H = 5.0, JH,H
=
=
3
2
3
2
CDCl3, 25 °C): δ = –5.3 (SiCH3), 14.3 (OCH2CH3), 18.4 [SiC- 7.0, JH,H = 13.0 Hz, 1 H, 4-CH2), 2.1 (dt, JH,H = 7.0, JH,H
(CH3)3], 21.2 (CH3), 26.0 [SiC(CH3)3], 28.3 [OC(CH3)3], 32.6 (C4),
3
2
13.0 Hz, 1 H, 4-CH2), 2.5 (dd, JH,H = 10.0, JH,H = 15.0 Hz, 1 H,
3
2
40.4 (CH2CO2Et), 49.3 (C3), 55.1 (C5), 60.5 (OCH2CH3), 62.7 CH2CO2Et), 2.6 (m, 1 H, 3-CH), 3.1 (dd, JH,H = 4.0, JH,H
=
(CH2OTBS), 64.0 (C2), 79.7 [OC(CH3)3], 125.9 (C2Ј, C6Ј), 129.0 15.0 Hz, 1 H, CH2CO2Et), 3.6 (d, 3JH,H = 6.0 Hz, 2 H, CH2OTBS),
3
(C3Ј, C5Ј), 136.2 (C4Ј), 141.0 (C1Ј), 154.8 (carbamate CO), 171.5 4.2 (q, JH,H = 7.0 Hz, 2 H, OCH2CH3), 4.3–4.4 (m, 1 H, 5-CH),
(ester CO) ppm. IR (film): ν = 2955, 2930, 2858, 1736 (C=O), 1694
4.8 (d, 3JH,H = 5.0 Hz, 1 H, 2-CH), 6.2 (d, 3JH,H = 3.0 Hz, 1 H, 3Ј-
˜
(C=O), 1514 (C=C), 1388, 1366, 1252, 1157, 1112, 836, 776 cm–1. CH), 6.3 (dd, JH,H = 2.0, JH,H = 3.0 Hz, 1 H, 4Ј-CH), 7.4 (mc,
3
3
UV/Vis (CH3CN): λmax (ε) = 212 (9874), 218 (9781), 266 (551), 273
(467 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for C27H45NO5Si [M
+ H]+ 492.31398; found 492.31408.
3JH,H = 1.0 Hz, 1 H, 5Ј-CH) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = –5.3 (SiCH3), 14.3 (OCH2CH3), 18.4 [SiC(CH3)3], 26.0
[SiC(CH3)3], 28.4 [OC(CH3)3], 32.7 (C4), 39.9 (CH2CO2Et), 45.7
(C3), 54.7 (C5), 57.4 (C2), 60.4 (OCH2CH3), 63.4 (CH2OTBS), 79.9
[OC(CH3)3], 106.2 (C3Ј), 110.2 (C4Ј), 141.4 (C5Ј), 154.2 (carbamate
tert-Butyl (2S,3S,5R)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-(2-
ethoxy-2-oxoethyl)-2-(3-methylphenyl)pyrrolidine-1-carboxylate
(7f): Yield: 42 mg, 89%, oil. Rf = 0.38 (Et2O/PE, 1:2). [α]2D4 = +20
CO), 155.6 (C2Ј), 171.7 (ester CO) ppm. IR (film): ν = 2955, 2931,
˜
2896, 2858, 1736 (C=O), 1697 (C=O), 1600 (C=C), 1506 (C=C),
1389, 1367, 1253, 1175, 1115, 838, 778 cm–1. UV/Vis (CH3CN):
λmax (ε) = 217 (11508 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for
C24H41NO6Si [M + H]+ 468.27759; found 468.27723.
1
(c = 1.08, CHCl3). H NMR (400 MHz, C2D2Cl4, 90 °C): δ = 0.1
(s, 3 H, SiCH3), 0.1 (s, 3 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3
3
[br., 9 H, OC(CH3)3], 1.3 (t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.9
3
3
2
(ddd, JH,H = 4.0, JH,H = 7.0, JH,H = 13.0 Hz, 1 H, 4-CH2), 2.1
(dt, JH,H = 8.0, 2JH,H = 13.0 Hz, 1 H, 4-CH2), 2.3–2.4 (m, 1 H, 3-
CH), 2.4 (s, 3 H, CH3), 2.5 (dd, JH,H = 10.0, JH,H = 15.0 Hz, 1
H, CH2CO2Et), 3.2 (dd, JH,H = 4.0, JH,H = 15.0 Hz, 1 H,
CH2CO2Et), 3.7 (mc, 2 H, CH2OTBS), 4.2 (q, JH,H = 7.0 Hz, 2 dichloromethane (0.1 , 1 equiv.). After 24 h, a saturated NH4Cl
General Procedure for the Removal of the tert-Butoxycarbonyl
Group: Anhydrous ZnBr2 (6.2 equiv.) was added under nitrogen at
room temp. to a solution of the appropriate pyrrolidine in dry
3
3
2
3
3
3
3
H, OCH2CH3), 4.4 (m, 1 H, 5-CH), 4.6 (d, JH,H = 6.5 Hz, 1 H,
solution was added. The aqueous phase was extracted three times
3
2-CH), 7.0–7.1 (m, 3 H, ArH), 7.2 (t, JH,H = 7.5 Hz, 1 H, 5Ј-CH) with ethyl acetate. The combined organic layers were dried with
ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = –5.3 (SiCH3), 14.4 MgSO4 and filtered, and the solvents were evaporated in vacuo.
(OCH2CH3), 18.4 [SiC(CH3)3], 21.6 (CH3), 26.0 [SiC(CH3)3], 28.2 The residue was dissolved in a small amount of diethyl ether, ad-
[OC(CH3)3], 32.7 (C4), 40.4 (CH2CO2Et), 49.2 (C3), 55.1 (C5), 60.6 sorbed on silica gel, and purified by flash column chromatography
(OCH2CH3), 62.7 (CH2OTBS), 64.3 (C2), 79.6 [OC(CH3)3], 123.1, on silica gel (1:100, w/w) with diethyl ether/petroleum ether (1:5, v/
126.8, 127.5, 128.2 (Car), 137.8 (C3Ј), 143.9 (C1Ј), 154.8 (carbamate v; containing 2% Et3N) as eluent.
CO), 171.6 (ester CO) ppm. IR (film): ν = 2956, 2930, 2858, 1736
˜
Ethyl
(2ЈS,4ЈS,5ЈS)-(4-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-
(C=O), 1695 (C=O), 1608 (C=C), 1389, 1366, 1254, 1175, 1135,
8 3 7 , 7 8 7 c m – 1 . U V / V i s ( C H 3 C N ) : λ m a x ( ε ) = 2 6 4
(677 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for C27H45NO5Si [M
+ H]+ 492.31398; found 492.31382.
phenylpyrrolidin-2-yl)acetate (8a): Yield: 38 mg, 90%, oil. Rf = 0.22
(Et2O/PE, 1:1 + 2% Et3N). [α]2D3 = +14 (c = 1.16, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 0.0 (s, 3 H, SiCH3), 0.0 (s, 3 H,
3
SiCH3), 0.9 [s, 9 H, SiC(CH3)3], 1.3 (t, JH,H = 7.0 Hz, 3 H,
3
2
tert-Butyl (2S,3S,5R)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-(2- OCH2CH3), 1.4 (dt, JH,H = 9.0, JH,H = 12.0 Hz, 1 H, 3Ј-CH2),
ethoxy-2-oxoethyl)-2-(2-methylphenyl)pyrrolidine-1-carboxylate
2.1 (br., 1 H, NH), 2.2–2.4 (m, 2 H, 3Ј-CH2, 4Ј-CH), 2.5 (dd, 3JH,H
= 8.0, JH,H = 15.5 Hz, 1 H, 2-CH2), 2.6 (dd, JH,H = 5.5, JH,H =
2
3
2
(7g): Yield: 65 mg, 87%, oil. Rf = 0.38 (Et2O/PE, 1:2). [α]2D4 = +47
1
3
2
(c = 1.10, CHCl3). H NMR (400 MHz, C2D2Cl4, 90 °C): δ = 0.1 15.5 Hz, 1 H, 2-CH2), 3.6 (dd, JH,H = 5.5, JH,H = 10.0 Hz, 1 H,
(s, 3 H, SiCH3), 0.1 (s, 3 H, SiCH3), 1.0 [s, 9 H, SiC(CH3)3], 1.3 [s, CH2OTBS), 3.6 (dd, 3JH,H = 5.0, 2JH,H = 10.0 Hz, 1 H, CH2OTBS),
3
3
9 H, OC(CH3)3], 1.3 (t, JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.9 (dt, 3.9 (mc, 1 H, 2Ј-CH), 4.1 (d, JH,H = 7.0 Hz, 1 H, 5Ј-CH), 4.1 (q,
2
3
3JH,H = 6.0, JH,H = 12.5 Hz, 1 H, 4-CH2), 2.2 (dt, JH,H = 7.5,
2JH,H = 13.0 Hz, 1 H, 4-CH2), 2.2–2.3 (m, 1 H, 3-CH), 2.4 (s, 3 H, NMR (75 MHz, CDCl3, 25 °C):
CH3), 2.6 (dd, 3JH,H = 10.0, 2JH,H = 15.0 Hz, 1 H, CH2CO2Et), 3.4 (OCH2CH3), 18.4 [SiC(CH3)3], 26.0 [SiC(CH3)3], 35.9 (C3Ј), 41.6
3JH,H = 7.0 Hz, 2 H, OCH2CH3), 7.2–7.4 (m, 5 H, ArH) ppm. 13C
δ
=
–5.3 (SiCH3), 14.4
3
2
(dd, JH,H = 4.0, JH,H = 15.0 Hz, 1 H, CH2CO2Et), 3.7 (mc, 2 H,
CH2OTBS), 4.2 (q, JH,H = 7.0 Hz, 2 H, OCH2CH3), 4.3–4.9 (m,
1 H, 5-CH), 4.9 (d, JH,H = 5.5 Hz, 1 H, 2-CH), 7.1–7.3 (m, 4 H, C ), 172.5 (C1) ppm. IR (film): ν = 3450, 3356, 3062, 3028, 2955,
(C2), 51.0 (C4Ј), 54.5 (C2Ј), 60.5 (OCH2CH3), 63.7 (C5Ј), 64.3
(CH2OTBS), 126.8 (p-Car), 127.0 (o-Car), 128.6 (m-Car), 145.2 (q
3
3
˜
ar
Eur. J. Org. Chem. 2009, 5549–5564
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5561

C. Enkisch, C. Schneider
FULL PAPER
2929, 2895, 2857, 1734 (C=O), 1602 (C=C), 1492 (C=C), 1471,
(300 MHz, C2D2Cl4, 90 °C): δ = 1.3 [s, 9 H, OC(CH3)3], 1.3 (t,
3
3
1255, 1183, 1095, 1029, 837, 776, 701 cm–1. UV/Vis (CH3CN): λmax 3JH,H = 7.0 Hz, 3 H, OCH2CH3), 2.0 (ddd, JH,H = 3.5, JH,H
=
=
2
3
3
(ε)
=
206 (9937 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for
7.0, JH,H = 13.0 Hz, 1 H, 4-CH2), 2.1 (ddd, JH,H = 8.0, JH,H
C21H35NO3Si [M + H]+ 378.24590; found 378.24566.
9.0, 2JH,H = 13.0 Hz, 1 H, 4-CH2), 2.3–2.4 (m, 1 H, 3-CH), 2.6 (dd,
3JH,H = 10.0, JH,H = 15.0 Hz, 1 H, CH2CO2Et), 3.2 (dd, JH,H
=
2
3
Ethyl (2ЈR,4ЈS,5ЈS)-(4-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-
2
3
2
4.0, JH,H = 15.0 Hz, 1 H, CH2CO2Et), 3.7 (dd, JH,H = 6.0, JH,H
= 11.0 Hz, 1 H, CH2OH), 3.8 (dd, JH,H = 5.5, JH,H = 11.0 Hz, 1
H, CH2OH), 4.2 (q, JH,H = 7.0 Hz, 2 H, OCH2CH3), 4.4–4.5 (m,
1 H, 5-CH), 4.6 (d, JH,H = 7.0 Hz, 1 H, 2-CH), 7.3–7.4 (m, 5 H,
phenylpyrrolidin-2-yl)acetate (8b): Yield: 32 mg, 84%, oil. Rf = 0.35
(Et2O/PE, 1:1 + 2% Et3N). [α]2D3 = –5 (c = 1.10, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 0.0 (s, 3 H, SiCH3), 0.0 (s, 3 H,
3
2
3
3
3
SiCH3), 0.9 [s, 9 H, C(CH3)3], 1.3 (t, JH,H = 7.0 Hz, 3 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.3
(OCH2CH3), 28.2 [OC(CH3)3], 32.8 (C4), 40.2 (CH2CO2Et), 49.3
(C3), 55.1 (C5), 60.6 (OCH2CH3), 62.6 (CH2OH), 64.7 (C2), 79.9
[OC(CH3)3], 126.0 (C4Ј), 126.9 (C2Ј, C6Ј), 128.4 (C3Ј, C5Ј), 143.9
3
3
2
OCH2CH3), 1.7 (ddd, JH,H = 8.0, JH,H = 9.5, JH,H = 12.5 Hz, 1
3
3
2
H, 3Ј-CH2), 1.9 (ddd, JH,H = 3.5, JH,H = 5.5, JH,H = 12.5 Hz, 1
3
2
H, 3Ј-CH2), 2.1–2.2 (m, 1 H, 4Ј-CH), 2.5 (dd, JH,H = 8.0, JH,H
16.0 Hz, 1 H, 2-CH2), 2.6 (dd, JH,H = 5.5, JH,H = 16.0 Hz, 1 H,
=
3
2
(C1Ј), 154.7 (carbamate CO), 171.5 (ester CO) ppm. IR (film): ν =
˜
3
2
2-CH2), 3.5 (dd, JH,H = 5.5, JH,H = 10.0 Hz, 1 H, CH2OTBS),
3459 (OH), 3031, 2978, 2932, 1735, 1692, 1604, 1477, 1455, 1392,
1367, 1304, 1253, 1177, 787, 700 cm–1. UV/Vis (CH3CN): λmax (ε)
= 201 (7684), 259 (79 mol–1 dm3 cm–1) nm. MS (ESI): m/z = 386
[M + Na]+, 749 [2 M + Na]+.
3.6 (dd, 3JH,H = 5.0, 2JH,H = 10.0 Hz, 1 H, CH2OTBS), 3.6–3.7 (m,
3
3
1 H, 2Ј-CH), 4.0 (d, JH,H = 7.5 Hz, 1 H, 5Ј-CH), 4.4 (q, JH,H
=
7.0 Hz, 2 H, OCH2CH3), 7.2 (mc, 1 H, ArH), 7.3 (mc, 2 H, ArH),
7.4 (mc, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
–5.3 (SiCH3), 14.4 (OCH2CH3), 18.4 [SiC(CH3)3], 26.0 [SiC-
(CH3)3], 34.5 (C3Ј), 41.7 (C2), 49.3 (C4Ј), 53.9 (C2Ј), 60.4
(OCH2CH3), 63.9 (CH2OTBS), 64.7 (C5Ј), 127.0 (p-Car), 127.3 (o-
Crystal Data for Methyl (2E,5S,6S)-6-[(tert-Butoxycarbonyl)-
amino]-6-(4-chlorophenyl)-5-(hydroxymethyl)hex-2-enoate (10): Em-
pirical formula C19H26ClNO5, M = 383.86, T = 293(2) K, λ =
71.073 pm, crystal system: triclinic, space group P1, unit-cell di-
mensions: a = 533.96(2), b = 1153.10(4), c = 1690.32(6) pm, α =
78.826(3), β = 86.028(2), γ = 88.086(2)°, V = 1.01835(6) nm3, Z =
2. ρ(calcd.) = 1.252 gcm–3, absorption coefficient 0.215 mm–1,
F(000) = 408, crystal size: 0.4ϫ0.1ϫ0.1 mm, Θ = 3.32–30.50°; in-
dex ranges: –7ՅhՅ7, –16ՅkՅ16, –24ՅlՅ24, reflections col-
lected: 21296, independent reflections: 12362 (Rint = 0.0237), com-
pleteness to Θ = 30.50°: 99.9%, refinement method: full-matrix le-
ast squares on F2, data/restraints/parameters: 12362/3/677, good-
ness-of-fit on F2: 0.817, final R indices [IϾ2σ(I)]: R1 = 0.0327, wR2
= 0.0479, R indices (all data): R1 = 0.0517, wR2 = 0.0503, absolute
structure parameter: 0.01(2).
C ), 128.3 (m-C ), 144.5 (q C ), 172.8 (C1) ppm. IR (film): ν =
˜
ar
ar
ar
3450, 3350, 3062, 3028, 2954, 2929, 2886, 2856, 1735 (C=O), 1603
(C=C), 1492 (C=C), 1471, 1256, 1189, 1162, 1101, 836, 776,
701 cm–1. UV/Vis (CH3CN): λmax (ε)
= 205 (8277), 210
(8216 mol–1 dm3 cm–1) nm. MS (ESI): m/z = 378 [M + H]+.
General Procedure for the Removal of the tert-Butyldimethylsilyl
Group: Tetrabutylammonium fluoride (1  in THF, 5.0 equiv.) was
added under nitrogen at room temp. to a solution of the appropri-
ate pyrrolidine in dry THF (0.02 ). After 40 min, a saturated
NH4Cl solution was added. The aqueous phase was extracted three
times with ethyl acetate. The combined organic layers were dried
with MgSO4 and filtered, and the solvents were evaporated in
vacuo. The residue was dissolved in a small amount of ethyl acetate,
adsorbed on silica gel, and purified by flash column chromatog-
raphy on silica gel (1:100, w/w) with diethyl ether/petroleum ether
(3:1, v/v) as eluent.
tert-Butyl (2S,3S,5R)-3-(Hydroxymethyl)-5-(2-methoxy-2-oxoethyl)-
2-phenylpyrrolidine-1-carboxylate (12): A solution of the appropri-
ate Mannich product (226 mg, 0.647 mmol) in dry THF (6.5 mL)
was treated with KOtBu (74 mg, 0.647 mmol) at 0 °C for 15 min.
Yield: 88 mg, 39%, white solid, dr Ͼ95:5. Rf = 0.10 (Et2O/PE, 5:1).
tert-Butyl (2S,3S,5S)-5-(2-Ethoxy-2-oxoethyl)-3-(hydroxymethyl)-2-
phenylpyrrolidine-1-carboxylate (9a): Yield: 49 mg, 89%, oil. Rf =
0.33 (Et2O/PE, 5:1). [α]2D3 = –69 (c = 1.33, CHCl3). 1H NMR
(300 MHz, C2D2Cl4, 90 °C): δ = 1.2 [s, 9 H, OC(CH3)3], 1.3 (t,
1
M.p. 80–82 °C. [α]2D2 = –2 (c = 1.0, CHCl3). H NMR (300 MHz,
2
C2D2Cl4, 90 °C): δ = 1.3 [s, 9 H, C(CH3)3], 1.9 (ddd, JH,H = 13.0,
3JH,H = 7.0, 3JH,H = 3.5 Hz, 1 H, 4-CH2), 2.1–2.2 (m, 1 H, 4-CH2),
2
3
3
2
3JH,H = 7.0 Hz, 3 H, OCH2CH3), 1.7 (dt, JH,H = 5.5, JH,H
=
2.3–2.4 (m, 1 H, 3-CH), 2.6 (dd, JH,H = 15.0, JH,H = 9.5 Hz,
2
3
1 H, CH2CO2Me), 3.2 (dd, JH,H = 15.0, JH,H = 4.0 Hz, 1 H,
CH2CO2Me), 3.7 (dd, 2JH,H = 10.5, 3JH,H = 6.0 Hz, 1 H, CH2OH),
3.8 (s, 3 H, OCH3), 3.7–3.8 (m, 1 H, CH2OH), 4.4 (mc, 1 H, 5-
13.5 Hz, 1 H, 4-CH2), 2.2–2.3 (m, 1 H, 3-CH), 2.4–2.5 (m, 1 H, 4-
3
2
CH2), 2.5 (dd, JH,H = 9.5, JH,H = 15.5 Hz, 1 H, CH2CO2Et), 3.4
(dd, 3JH,H = 3.5, JH,H = 15.5 Hz, 1 H, CH2CO2Et), 3.7 (dd, 3JH,H
2
3
2
3
2
CH), 4.6 (d, JH,H = 7.0 Hz, 1 H, 2-CH), 7.3–7.4 (m, 5 H, ArH)
= 6.0, JH,H = 10.5 Hz, 1 H, CH2OH), 3.8 (dd, JH,H = 7.0, JH,H
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 28.2 [C(CH3)3],
32.9 (C4), 40.1 (CH2CO2Me), 49.3 (C3), 51.8 (OCH3), 55.2 (C5),
62.6 (CH2OH), 64.7 (C2), 79.9 [C(CH3)3], 126.0 (C4Ј), 127.0 (C2Ј,
C6Ј), 128.5 (C3Ј, C5Ј), 143.8 (C1Ј), 154.7 (carbamate CO), 171.9
= 10.5 Hz, 1 H, CH2OH), 4.2 (q, 3JH,H = 7.0 Hz, 2 H, OCH2CH3),
3
4.5 (mc, 1 H, 5-CH), 4.7 (d, JH,H = 4.0 Hz, 1 H, 2-CH), 7.2 (br.
3
d, JH,H = 7.0 Hz, 2 H, 2Ј-CH, 6Ј-CH), 7.3 (mc, 1 H, 4Ј-CH), 7.3
(br. t, JH,H = 7.0 Hz, 2 H, 3Ј-CH, 5Ј-CH) ppm. 13C NMR
3
(ester CO) ppm. IR (KBr): ν = 3572, 3501, 3030, 3012, 2979, 2904,
˜
(100 MHz, CDCl3, 25 °C): δ = 14.3 (OCH2CH3), 28.0 [OC(CH3)3],
31.9 (C4), 39.5 (CH2CO2Et), 50.0 (C3), 55.4 (C5), 60.5
(OCH2CH3), 64.3 (CH2OH), 65.4 (C2), 79.7 [OC(CH3)3], 125.6
(C4Ј), 126.8 (C2Ј, C6Ј), 128.5 (C3Ј, C5Ј), 145.1 (C1Ј), 154.3 (carba-
2873, 1732, 1724, 1692, 1674, 1604, 1493, 1476, 1458, 1445, 1400,
1382, 1365, 1313, 1179, 1155, 1136, 1074, 1059, 972, 772, 702 cm–1.
UV/Vis (CH3CN): λmax (ε)
= 205 (11184), 252 (402), 258
(422 mol–1 dm3 cm–1) nm. MS (ESI): m/z = 350 [M + H]+, 372 [M
mate CO), 172.0 (ester CO) ppm. IR (film): ν = 3448 (OH), 2978,
˜
+ Na]+.
1733, 1692, 1477, 1455, 1392, 1367, 1254, 1167, 1133, 788, 763,
701 cm–1. UV/Vis (CH3CN): λmax (ε)
= 201 (14064), 259
Crystal Data for tert-Butyl (2S,3S,5R)-3-(Hydroxymethyl)-5-(2-
methoxy-2-oxoethyl)-2-phenylpyrrolidine-1-carboxylate (12): Empir-
ical formula C19H27NO5, M = 349.42, T = 130(2) K, λ =
(281 mol–1 dm3 cm–1) nm. HRMS-ESI: calcd. for C20H29NO5 [M +
Na]+ 386.19379; found 386.19407.
tert-Butyl (2S,3S,5R)-5-(2-Ethoxy-2-oxoethyl)-3-(hydroxymethyl)-2- 71.073 pm, crystal system: monoclinic, space group: P2(1), unit-cell
phenylpyrrolidine-1-carboxylate (9b): Yield: 54 mg, 98%, oil. Rf =
dimensions: a = 1565.12(2), b = 592.100(10), c = 2011.51(3) pm, α
0.25 (Et2O/PE, 5:1). [α]2D3 = –0.7 (c = 5.62, CHCl3). 1H NMR
= γ = 90°, β = 94.6290(10)°, V = 1.85800(5) nm3, Z = 4, ρ(calcd.)
5562
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5549–5564

Stereodivergent Synthesis of Highly Substituted Pyrrolidines
= 1.249 gcm–3, absorption coefficient 0.090 mm–1, F(000) = 752,
crystal size: 0.4ϫ0.3ϫ0.1 mm, Θ = 2.88–30.51°, index ranges:
–22ՅhՅ22, –8ՅkՅ8, –28ՅlՅ27, reflections collected: 31243,
independent reflections: 11279 (Rint = 0.0265), completeness to Θ
= 30.51°: 99.7%, refinement method: full-matrix least squares on
F2, data/restraints/parameters: 11279/1/667, goodness-of-fit on F2:
0.950, final R indices [IϾ2σ(I)]: R1 = 0.0356, wR2 = 0.0730, R
indices (all data): R1 = 0.0484, wR2 = 0.0759, absolute structure
parameter: –0.2(4).
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Support of this work through a doctoral scholarship to C. E.
granted by the German National Academic Foundation (Studien-
stiftung des Deutschen Volkes) is gratefully acknowledged. We
would like to thank PD Dr. Stefan Immel (TU Darmstadt) for the
DFT calculations and Dr. Peter Lönnecke (University of Leipzig)
for solving the X-ray crystal structures of the Mannich product 10
and the 2,5-cis-configured pyrrolidine 12.
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5563

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Received: July 15, 2009
Published Online: September 25, 2009
5564
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5549–5564